This study was to investigate the predictive power of IL28B SNPs for on-treatment responses and SVR in treatment-naïve patients with GT1-HCV chronic infection.Single nucleotide polymorphisms (SNPs) of IL28B in 191 treatment-naïve patients with GT1-HCV chronic infection who received PegIFN/RBV. In these patients, rapid virological response (RVR), early virological response (EVR) and SVR were achieved in 69.6%, 95.8% and 68.6% of the patients, respectively. Multivariate analysis  indicated age , low baseline viral load  and CC genotype of rs12979860  but no other SNPs were independent predictors for SVR. In addition, none of the ten SNPs examined were associated with baseline viral load and stages of liver fibrosis. Regarding RVR, low baseline viral load  and CC genotype of rs12979860  were two critical predictors. As for EVR, only CC genotype of rs12979860  was the predictor. Similarly, for end of treatment response (ETR), CC genotype of rs12979860  was the only predictor. For patients with RVR, only low baseline viral load  could predict the SVR. For patients without RVR, only rs12979860  was the predictor for SVR.We analyzed ten SNPs of IL28B SNP for genetic testing in treating patients of GT1-HCV chronic infection.rs12979860 is the critical predictor for RVR, EVR, ETR and SVR in treatment-naïve patients of GT1-HCV chronic infection. Furthermore, this SNP is the only predictor for SVR in patients without RVR. These results have provided evidence that rs12979860 is the ideal  A combination therapy of pegylated interferon-alpha and ribavirin (PegIFN/RBV) is a well-accepted standard of care for patients with chronic hepatitis C (CHC) Interluekin-28B (IL28B) were significantly correlated with SVR when patients were treated with PegIFN/RBV IL28B was reported highest in Asians and lowest in African-Americans. In addition, the prevalence rates of cc genotype of rs1297860 paralleled with the SVR in each population IL28B also correlated with the spontaneous clearance of hepatitis C virus IL28B before deciding on treatment strategies has been proposed IL28B were also found to be highly associated with SVR, like rs8099917 Host genetic factors on the treatment efficacy for chronic hepatitis C were proposed a long time ago due to the ethnic differences in the treatment outcome. Recent genome-wide associated studies have explored this issue and demonstrated strong evidence that single nucleotide polymorphisms (SNPs) of IL28B for RVR, EVR and SVR in a cohort of patients with GT1-HCV chronic infection treated with PegIFN/RBV from a large medical center.We investigated these issues and tried to increase our understanding of the predictive ability of 10 SNPs of We analyzed a prospective cohort of 213 consecutive adult Taiwanese treatment-naïve patients with chronic hepatitis C virus genotype 1 who visited HCV team of Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, and received 24 weeks of combination therapy with PegIFN/RBV between February 2002 and December 2008, and who agreed to provide blood samples for the human genome study. Patients with decompensated liver disease, hepatoma, co-infection with hepatitis B virus or with human immunodeficiency virus, with apparent autoimmune hepatitis and alcoholic liver disease were excluded from this cohort. All patients included in the study had received liver biopsies that were evaluated by one pathologist using the Metavir scoring system. HCV genotype was determined by a genotype specific probe based assay in the 5′ untranslated region . In these 213 patients, we excluded 22 patients who did not fit the 80/80/80 adherence rule , with a final case number of 191 .10 reduction of viral load at week 12 after starting treatment as EVR, and undetectable virus at the end of treatment as ETR.Definitions of response to treatment were undetectable serum HCV-RNA levels 24 weeks after cessation of treatment as SVR, undetectable serum HCV-RNA levels at 4 week after starting treatment as RVR, at least two-log2IU/ml) or COBAS TaqMan HCV Test . If non-detection of HCV-RNA by VERSANT HCV RNA 3.0. Assay, it would be further tested by COBAS® AMPLICOR HCV Test, v2.0 .The HCV-RNA levels in this study were measured using a commercial quantitative polymerase chain reaction (PCR) assay VERSANT HCV RNA 3.0. Assay  and used in the PCR reaction. Aliquots of the PCR product were genotyped with allele specific probe of SNPs using real time PCR (ABI). Ten SNPs of IL28B including rs12979860, rs11881222, rs4803219, rs8099917, rs12980275, rs8105790, rs7248668, rs10853728, rs8103142 and rs28416813 were chosen according to previous reports Anti-coagulated peripheral blood was obtained from HCV patients. Genomic DNA was isolated from EDTA anti-coagulated peripheral blood using the Puregene DNA isolation kit  as previously describedAll patients in this study had provided written informed consent. This study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethical committees of Chang Gung Memorial Hospital.t-test. Univariate and multivariate logistic regression analyses for predictors of sustained virological response were conducted using patients' demographic, clinical variables and IL28B SNPs. The clinical variables included gender, age, viral load of HCV-RNA, Metavir fibrosis stage, body mass index (BMI), Glycohemoglobin (HbA1c), albumin, aspartate transaminase, alanine transaminase, bilirubin, gamma-glutamyl transpeptidase and alkaline phosphatase.Linkage disequilibrium (LD) between marker loci was assessed and haplotype blocks were constructed using Haploview 4.1. Chi-square tests and Fisher's exact probability tests were used as appropriate to compare the categorical variables of the groups. Continuous variables were expressed as means and standard deviations (SDs) and compared using Mann-Whitney U test or Student's P values less than 0.05 by the two-tailed test were considered statistically significant. Variables that achieved a statistical significance less than 0.10 in the univariate analysis were entered into multivariate logistic regression analysis to identify the significant independent predictive factors. All statistical analyses were performed with statistical software SPSS for Windows .The odds ratios (OR) and 95% confidence intervals (95% CI) were also calculated. Breslow-Day test and Cochran's-Mantel-Haenszel test were used to estimate the homogeneity of odds ratios (ORs) between stratified groups. All 6 IU/mL), less fibrosis stage (Metavir fibrosis score F0–F2), low body mass index (BMI), lower gamma-glutamyl transferase (GGT), RVR and EVR  patients enrolled in this prospective cohort were shown in  and EVR . Ten SNPilibrium  and rs12ilibrium .6 IU/ml) became the significant predictors for SVR by the multivariate analysis . Therefore, in addition to the findings that this SNP had no relationship with baseline viral load, the impact of the SNP on SVR remained similar either in the group of high baseline viral load or low baseline viral load.As shown in P <0.001). We evaluated the influence of these SNPs on the SVR in these two groups of patients. In patients with RVR, only low baseline viral load was a significant predictor for SVR but not any SNPs of IL28B or other clinical parameters . Another locus, rs28416813, was a G to C substitution at 37 base pairs upstream of the translation initiation siteBased on previous reports on the SNPs of However, we found the genotype of rs12979860, but not other SNPs, together with age and viral load became the predictors of SVR. rs12979860 is the frequently mentioned SNP of IL28B related to SVR IL28B, the results from previous reports were not consistent. Some reports claimed the baseline viral load was correlated with the genotype of the SNP but others did not IL28B could predict the SVR with similar predictive ability. Therefore, in our cohort, SNP of IL28B was only related to the treatment outcome but was not related to the viral load.Concerning the relationship between baseline viral load and SNPs of IL28B is related to the immune responses after interferon-plus RBV treatment A customized therapy for chronic hepatitis C based on genotype and treatment viral response is the current treatment strategy Another interesting observation in our study was the different impact of the CC genotype of rs12979860 on the SVR in patients with or without RVR. In patients with RVR, only baseline viral load but not the genotype of rs12979860 could predict the SVR. This is an interesting observation. The possible explanation is the CC genotype of rs12979860 led to the RVR with odds ratio of 10.52. As a result, the majority of patients with RVR were CC genotypes. Therefore, the CC genotype lost their predictive ability for SVR in this patient group with high prevalence of CC genotype. On the contrary, in patients without RVR, only the genotype of rs12979860 but not the baseline viral load could predict the SVR. This group of patients without RVR was with lower prevalence of CC genotype. Therefore, the CC genotype could continue its influence and therefore predict the SVR in this group of patients. This observation was quite similar to the recent report about genotype 2/3 HCV infected patients who received treatment that the genotype of rs12979860 is a single predictor for SVR in patients without RVR IL28B would be a suitable genetic testing before starting treatment for patients with GT1-HCV chronic infection.Since the discovery of the strong association between SNPs of IL28B and treatment outcome of chronic hepatitis C, a consideration of personalized approach for treatment of chronic hepatitis C based on these SNPs had been proposed On the other hand, though a strong association between IL28B polymorphism and SVR had been repeated reported, the underlying mechanisms are still unclear. Recent in-vitro report had shown that IL28B could inhibit HCV replication in a dose- and time- dependent manner and through the JAK-STAT pathway The limitation of this study was the retrospective nature of the analysis. However, it is common to all the papers published on this issue. The other limitation was that we had excluded the patients who didn't adhere to the 80/80/80 principle in order to investigate the real effects of SNPs on the treatment response. However, this exclusion would possibly ignore the possibilities that some patients without 80/80/80 adherence were due to the effect of these SNPs though till now there was no such report. Prospective controlled studies would be necessary to evaluate the influence of different SNPs of IL28B gene, especially rs12979869 and rs8077717, on treatment outcome of patients with chronic hepatitis C.IL28B in patients with GT1 HCV infection treated with PegIFN/RBV. Furthermore, we also demonstrated different impact of baseline viral load and genotype of rs12979860 on SVR in patients with or without RVR. Based on these results, we suggested that the genotyping of rs12979860 is the suitable target for genetic testing before treatment for patients with GT1-HCV chronic infection.In conclusion, our data demonstrated that the genotype of rs12979860 is the most powerful predictor for RVR, EVR, ETR and SVR among ten SNPs of


Seventy percent of the AIDS patients have neurological complications. Seizures are one of the complications and can occur at any stage. Seizures can be life-threatening and treatment with anticonvulsants is warranted. The therapeutic dilemma occurs in this case because of the interactions between the anticonvulsants, especially the first generation anticonvulsants, with antiretroviral agents resulting in significant side-effects including toxicity. The non-availability of second-generation anticonvulsants and cost constraints further limit the choices for the physicians. In this mini-review, we discuss the management of AIDS related seizures with emphasis on the drug–drug interactions between anticonvulsants and antiretroviral agents. We will also address the future directions and the need for prospective studies with second-generation anticonvulsants. Neurological symptoms are commonly encountered in HIV patients, which range from meningitis, encephalopathy, and neoplasm to seizures , 2. New The diagnosis of seizures in HIV patients includes neuroimaging, lumber puncture, and electroencephalogram (EEG). Harden et al. showed low amplitude EEG in AIDS dementia complex . GabzudaIn this mini-review article, we discuss the role of anticonvulsants in seizure management in AIDS patients.Treatment with anticonvulsants in AIDS related seizures is necessary to prevent recurrent breakthrough seizures and to improve the quality of life of these patients.There are several studies, which report the concomitant use of antiepileptic drugs (AEDs) in patients on antiretroviral therapy (ART). Birbeck et al. discussed the evidence-based guidelines from the International League against Epilepsy (ILAE) and the American Academy of Neurology (AAN) for antiepileptic drug selection for people with HIV/AIDS. The AAN and the ILAE formed a joint panel to evaluate the literature on concurrent usage of AEDs and antiretroviral drugs (ARVs). From 1950 to 2010, they queried six major databases and found 4,480 articles with potential data. These articles were reviewed first by their titles and abstract. The remaining 68 full articles were reviewed. Three Class III articles comprising 434,100,550 subjects identified a new onset seizure in 2.6–61% of HIV positive patients. In HIV patients who had not initiated ARV therapy, three class III studies of 255,101,272 patients indicated a 6.7–52.5% occurrence of peripheral neuropathy symptoms. This increased to 17–55% of HIV patients developing peripheral neuropathy symptoms after ARV initiation in two class III studies of 173, 2762 subjects. Patients receiving ritonavir/atazanavir may require an increase in lamotrigine to maintain levels, by as much as another 50% of the current lamotrigine dosage. Patients receiving valproic acid may require a reduction of zidovudine dose to maintain serum concentration of valproic acid. Patients may not require dosage adjustments if they are receiving valproic acid and efavirenz, raltegravir/atazanavir and lamotrigine, or raltegravir and midazolam.The review of seven articles showing a correlation of enzyme-inducing antiepileptic drugs (EI-AEDs) and decreased viral suppression rates and subtherapeutic ARV levels led the panel to caution the use of EI-AEDs in patients with ARV therapy with protease inhibitors (PIs) or non-nucleoside reverse transcriptases (NNRTIs). When EI-AEDs need to be used, monitoring is recommended .Siddiqi et al. conducted a literature review of the diagnosis and treatment of new onset seizures in patients with HIV. There are many potential causes of seizures in HIV positive patients, including infections, metabolic disturbances, medication side-effects, drug–drug interactions, and cerebrovascular disease. The etiology is unidentifiable in 28% of HIV positive patients. In the case of an acute symptomatic seizure due to an identifiable cause, AED treatment is recommended for 3–6 months with subsequent reassessment.in vitro studies have shown valproic acid in HIV positive patients to stimulate HIV replication, in vivo studies have not shown this.For chronic management of seizures, the choice of AED must take into consideration possible interactions with the patient’s ARV regimen. For patients treated with PIs and NNRTIs, studies recommend avoiding EI-AEDs, including primidone phenytoin, phenobarbital, and carbamazepine. However, in resource-limited settings, EI-AEDs are the most commonly used, and in some cases, are the only available options. Carbamazepine and phenytoin demonstrated a reduced half-life of the NNRTI nevirapine. While previous The authors state that when available, the recommended AEDs are levetiracetam followed by lacosamide, gabapentin, and pregabalin. All four are renally metabolized and do not interact with any AEDs or ARVs. Levetiracetam and lacosamide can be administered orally or intravenously, but levetiracetam has the additional benefit of being more moderately priced and does not need to be avoided in patients with second and third degree atrioventricular block, which is the case with lacosamide. Gabapentin and pregabalin can be administered only orally, and the costs range from moderate to expensive. In the event of medically refractory epilepsy, surgery may be an option for patients with focal brain lesions. Vagal nerve stimulators can be an option in poor surgical candidates but these require a higher level care center and greater costs .N = 5 of 10), focal epilepsy (N = 1), status epilepticus secondary to herpes simplex virus (HSV) encephalitis (N = 1), seizures secondary to PML (N = 1), trigeminal neuralgia (N = 1), or distal motor sensory neuropathy (N = 1). There were no statistically significant differences in demographics, with the age at diagnosis (32 years study group vs. 33 years control group), age at first AED/ARV overlap (42 vs. 47 years), female gender (10 vs. 12%), CD4 count at first AED/ARV overlap (377 vs. 397), and months of AED/ARV overlap (20 vs. 27). The EI-AED group had higher percentages than controls of overlap of intervals with one or more ARV intervals below Cmin . This analysis excluded six below the reference range EI-AED levels in EI-AED/ARV overlap periods, there was a statistically significant difference when 60% of the EI-AED group AED/ARV overlaps with one or more ARV levels below Cmin (vs. 23.3% p = 0.008). The authors concluded that there was a substantial impact of EI-AEDs on ARV drug levels  or a protease inhibitor  were included. Ten study subjects were identified from the US Military HIV Natural History Study of 5,300 current and retired military members and beneficiaries with HIV aged at least 18 years. Patients were included if they had been on an ARV regimen for at least 6 months, on an EI-AED for at least 28 consecutive days during that period, and if serum EI-AED and ARV levels suggested medication compliance. Twenty-five control subjects with 30 overlap periods were identified as individuals that were not on an EI-AED (NEI-AED) and an ARV who met the inclusion criteria. In the study group, there were 16 periods of combined ARV/EI-AED use, most commonly for an unspecified seizure disorder  and calcium channel blockers  were associated after 12 months of therapy with increased CD4 T cell levels (p < 0.05), and had no change in CD8 T cell levels. The authors concluded that while patients had received high cumulative doses of AEDs with concurrent ART, there was a potential benefit to immune status and was comparatively safe  replication. However, in one included study, six of nine patients followed for 1–13 weeks did not show increase in viral loads. The authors advised avoidance or cautious use of phenytoin, if necessary , opportunistic infections (two of six studies), and idiopathic (two of six studies). In two of the studies that delineated between the different causes of opportunistic infections, cerebral toxoplasmosis was the most commonly reported (~30%). Six studies indicated the correlation of hypoalbuminemia increasing the free concentrations of highly protein bound drugs. AED examples were phenytoin, carbamazepine, clonazepam, and diazepam and ARV examples were delavirdine efavirenz, saquinavir ritonavir, nelfinavir, lopinavir, and amprenavir. Two cases of HIV-hypoalbuminemia reported increased free phenytoin concentrations in 21 patients and increased phenytoin and valproic acid levels, respectively. HIV hypergammaglobulinemia was noted in four cases to predispose patients to potentially life threatening hypersensitivity reactions. One of these reported that 14% of HIV positive patients receiving phenytoin had hypersensitivity reactions, including Stevens – Johnson syndrome. Finally, five studies included the possible correlation of valproic acid to stimulate ecessary .in vivo studies of safety and efficacy of the use of AEDs in HIV positive individuals . This may lead to increased free drug levels which in turn increases side-effects and toxicity. VPA has also been shown to stimulate the viral replication of HIV through the reduction of intracellular levels of glutathione and VPA has been reported to stimulate CMV replication. In patients receiving AEDs and ARVs, the authors suggest careful monitoring of viral load, disease progression, and AED serum levels. The authors conclude that additional controlled trials of pharmacokinetic and pharmacodynamics interactions are needed as well as ividuals .The newer anticonvulsants, if available, should be used to minimize interactions with PIs and NNRTIs. The choices include levetiracetam, lacosamide, gabapentin, and pregabalin, which are renally excreted. Significant decrease in lamotrigine concentrations may be seen when used with ritonavir-based regimens. Viral load should be monitored closely if treated with valproic acid. Enzyme-inducing antiepileptic medications should be used with caution because of side-effects and drug–drug interactions with antiretroviral agents.Limited data are available regarding the use of newer anticonvulsants because of a lack of availability in some countries and costs restraints in this patient subgroup. There is a need for larger prospective trials in order to provide more data about the role of newer anticonvulsants in HIV related seizures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Rates of cardiovascular disease are higher among HIV-infected patients as a result of the complex interplay between traditional risk factors, HIV-related inflammatory and immunologic changes, and effects of antiretroviral therapy (ART). This study prospectively evaluated changes in cardiovascular biomarkers in an underrepresented, racially diverse, HIV-1-infected population receiving abacavir/lamivudine as backbone therapy.HLA-B*5701-negative adults without major resistance mutations to study drugs. We evaluated changes from baseline to weeks 4, 12, 24, 48, and 96 in interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble vascular adhesion molecule-1 (sVCAM-1), d-dimer, plasminogen, and fibrinogen. Biomarker data were log-transformed before analysis, and changes from baseline were described using geometric mean ratios.This 96-week, open-label, randomized, multicenter study compared once-daily fosamprenavir/ritonavir 1400/100 mg and efavirenz 600 mg, both with ABC/3TC 600 mg/300 mg, in antiretroviral-naïve, This study enrolled 101 patients : 32% female, 60% African American, and 38% Hispanic/Latino; 66% (67/101) completed 96 weeks on study. At week 96, levels of IL-6, sVCAM-1, d-dimer, fibrinogen, and plasminogen were lower than baseline in both treatment groups, and the decrease was statistically significant for sVCAM-1 (fosamprenavir/ritonavir and efavirenz), d-dimer (fosamprenavir/ritonavir and efavirenz), fibrinogen (efavirenz), and plasminogen (efavirenz). Values of hs-CRP varied over time in both groups, with a significant increase over baseline at Weeks 4 and 24 in the efavirenz group. At week 96, there was no difference between the groups in the percentage of patients with HIV-1 RNA <50 copies/mL  by ITT missing-equals-failure analysis. Treatment-related grade 2–4 adverse events were more common with efavirenz (32%) compared with fosamprenavir/ritonavir (20%), and median lipid concentrations increased in both groups over 96 weeks of treatment.In this study of underrepresented patients, treatment with abacavir/lamivudine combined with either fosamprenavir/ritonavir or efavirenz over 96 weeks, produced stable or declining biomarker levels except for hs-CRP, including significant and favorable decreases in thrombotic activity (reflected by d-dimer) and endothelial activation (reflected by sVCAM-1). Our study adds to the emerging data that some cardiovascular biomarkers are decreased with initiation of ART and control of HIV viremia.NCT00727597ClinicalTrials.gov identifier  Cardiovascular disease (CVD) is the leading cause of death among Americans , is of pIn the United States, racial and ethnic minorities are disproportionately affected by the HIV/AIDS epidemic. Many of the traditional risk factors for CVD such as hypertension, diabetes, and obesity are higher in the African-American population . ClinicaThe present study was a randomized trial comparing ritonavir-boosted fosamprenavir (FPV/r) versus EFV, both in combination with abacavir/lamivudine (ABC/3TC), in an ART-naïve, HIV-infected population that is often underrepresented in clinical trials in the United States. The primary endpoint was a measure of tolerability, and the study included a prospective, real-time evaluation of changes of pre-specified cardiovascular biomarkers over 96 weeks. The final, 96-week analysis of the trial with a focus on cardiovascular biomarker data is described in this report.HLA-B*5701-negative, and had a screening HIV-1 RNA >5000 copies/mL. Patients were required to be of minority race or ethnicity. Females of child-bearing potential could not be pregnant or breastfeeding at screening and had to agree to use a suitable form of contraception, including abstinence, double barrier method, or intrauterine device, throughout the study. Hormonal contraception was not recommended for female patients taking FPV/r because of decreased efficacy of contraception and increased risk of hepatic transaminase elevation.This randomized, open-label, multi-centered, pilot study enrolled patients ≥18 years of age who were ART-naïve (≤14 days of treatment with any ART), 3, or calculated creatinine clearance <50 mL/min via Cockcroft-Gault equation at screening. Use of immunomodulators , any vaccinations, systemic cytotoxic chemotherapy, or investigational therapy was prohibited within 28 days of study entry. Patients were also excluded if their screening HIV-1 genotype indicated the presence of specific mutations. In the reverse transcriptase (RT) region, exclusionary mutations were those associated with resistance to abacavir, lamivudine, or efavirenz , or a combination of two or more thymidine analog mutations  that included changes at either L210 or T215. Within the protease region, exclusionary mutations were those associated with resistance to fosamprenavir or ritonavir  or the combination of V32I + I147V. There were no restrictions on screening CD4 cell count.Patients were excluded if they had an active or acute CDC Clinical Category C event (AIDS-defining illness) within 28 days of screening or had chronic hepatitis B infection (HBsAg+), hepatitis C infection requiring active treatment, clinically-relevant pancreatitis or hepatitis, AST or ALT >5× upper limit of normal, any grade 4 laboratory abnormality, hemoglobin <8 g/dL, platelet count <50,000/mmAll patients provided written informed consent to participate in the study, and the protocol was approved by the institutional review board for each study site. Eligible patients were randomized 1:1 to receive either FPV 1400 mg once daily  plus ritonavir 100 mg once daily  or EFV 600 mg once daily . All patients also received ABC 600 mg + 3TC 300 mg once daily . Randomization was stratified by screening HIV-1 RNA <100,000 and ≥100,000 c/mL.For the virology HIV-1 genotypic analysis, virologic failure was defined as having either virologic non-response (failure to achieve HIV-1 RNA <400 c/mL by Week 24) or confirmed virologic rebound (reduction of HIV RNA to <400 c/mL by Week 24 with a subsequent increase to ≥400 c/mL on two consecutive occasions 2 to 4 weeks apart.) In the case of clinically-suspected hypersensitivity to ABC, patients were permitted to substitute ABC/3TC with another suitable dual nucleoside/nucleotide RT inhibitor combination chosen by the site investigator and remained in the study.Clinical, safety, and laboratory evaluations were performed at screening, baseline, and at weeks 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96 including measurements of plasma HIV-1 RNA, CD4 cell count, hematology, and blood chemistry. HIV-1 RNA was measured using the standard or ultrasensitive Roche Amplicor HIV-1 Monitor assay . A fasting lipid panel was done at baseline and every 24 weeks thereafter through week 96. All laboratory tests were performed centrally by Quest Diagnostics . Adverse events (AEs) and laboratory toxicities were graded using the 2004 Division of AIDS Toxicity Grading Scale.Biomarkers were assessed in real-time using whole blood, plasma, or serum samples collected at baseline and at weeks 4, 12, 24, 48, and 96. Six biomarkers were assessed including high-sensitivity C-reactive protein [hs-CRP] and interleukin-6 [IL-6] which are associated with inflammation; d-dimer, plasminogen, and fibrinogen which are associated with thrombogenesis; and sVCAM-1 which is associated with endothelial activation. Biomarkers were assayed centrally by Quest Diagnostics . sVCAM-11 and IL-6 were analyzed by quantitative sandwich ELISA; plasminogen by double antibody ELISA; fibrinogen by photo-optical method; d-dimer by immunoturbidimetry; and hs-CRP by fixed-time nephelometry. All assays were performed according to the manufacturers’ recommendations and used their normal ranges.The pre-specified primary endpoint of this study was the time to switch of comparator drugs (FPV/r or EFV) or time to development of any treatment-related grade 3–4 AE. Pre-specified secondary endpoints included change from baseline in biomarkers of cardiovascular risk; measures of virologic efficacy; incidence, severity, and causality of adverse events and laboratory abnormalities; and change from baseline in CD4 cell count and fasting lipids. Patients experiencing virologic failure were also evaluated for treatment-emergent viral resistance mutations.A sample size of 100 patients was planned for this pilot study based on practical considerations. Analyses were performed using the intent-to-treat exposed (ITT-E) population that included any enrolled patient who took at least one dose of study medication. Biomarker data was log-transformed prior to analysis (due to the highly skewed nature of the data), and the change from baseline was assessed using geometric mean ratios with 95% confidence intervals.Efficacy results were assessed using missing or discontinuation equals failure (MD = F) analyses, in which missing assessments were considered failures, and observed analyses, in which missing assessments at any scheduled time point were considered unevaluable and were not imputed. The primary endpoint was compared using the log-rank test between the two treatment groups. Virologic, immunologic, and safety results were described using summary statistics.3 . Cardiovascular risk factors were generally similar between the two groups. Sixty-six percent of patients completed 96 weeks on study , ran from July 2008 (first patient first visit) through March 2011 (last patient last visit). Baseline characteristics are shown in Table P = 0.656). Of the 4 patients in the FPV/r-containing group, 1 switched from FPV/r to EFV after 14 days due to an adverse event, 1 had grade 3 hypertriglyceridemia at day 57 on treatment, 1 had a fatal cardiac arrest at day 200, and 1 had grade 3 worsening hyperlipidemia at day 340. The cardiac arrest occurred shortly after the Week 24 study visit in a 49-year old Central/South Asian male, non-smoker, with a history of hypercholesterolemia and uncontrolled hypertension; on autopsy, death was attributed to atherosclerotic coronary artery disease resulting from 95% narrowing of the left anterior descending coronary artery by necrotic plaque. In the EFV-containing group, 3 of 6 patients experienced grade 3 AEs  and 3 switched from EFV to FPV/r  for adverse events. There was no apparent relationship between the primary endpoint and baseline viral load.The primary endpoint of this study was the time to switch of comparator drugs (FPV/r or EFV) or development of any treatment-related grade 3/4 AE. In the FPV/r-containing group, 4/51 (8%) of patients reached the latter endpoint compared with 6/50 (12%) in the EFV-containing group (3 (interquartile range: 136 to 311 cells/mm3) in the FPV/r group and +235 cells/mm3 (range: 137 to 294 cells/mm3) in the EFV group.There was no difference between treatment groups in the percentage of patients who achieved HIV RNA <50 c/mL at Week 96 using either an ITT -:MD = F or an observed analysis Figure . PatientFor the virology analysis, by week 24, all on-study subjects had virologically suppressed to <400 copies/ml. Confirmed virologic failure occurred in 7 patients (14%) taking FPV/r and 6 patients (12%) taking EFV. In the FPV/r-containing group, the following treatment-emergent viral mutations in RT were observed at virologic failure: M184V (in virus from 2 patients); while virus from another patient developed a treatment-emergent secondary protease mutation V77I (per IAS-USA guidelines). In the EFV-containing group, the following treatment-emergent viral mutations in RT were observed at virologic failure: M184I/M (in virus from 1 patient), K65R (virus from 1 patient), and K103N (virus from 2 patients). Interestingly, virus from 1 patient experiencing virologic failure while taking EFV also developed several treatment-emergent secondary PI-associated mutations.Treatment-related serious AEs occurred in 2 patients taking FPV/r (cardiac arrest and suspected drug hypersensitivity to ABC) and in 3 patients taking EFV . Through Week 96, 20% (10/51) of patients taking FPV/r and 32% (16/50) taking EFV experienced treatment-related grade 2–4 AEs. The most common AEs (FPV/r vs EFV) were rash (2% vs 8%), dizziness (0% vs 8%), and hypercholesterolemia (4% vs 4%). Three patients in each group (6%) experienced treatment-related grade 3–4 adverse events (only hypercholesterolemia occurred in >1 patient). Treatment-emergent grade 3–4 laboratory abnormalities emerged in 31% (16/51) of patients taking FPV/r and 24% (12/50) of patients taking EFV; the most common abnormalities involved cholesterol, creatine kinase, and total neutrophils.Median concentrations of total, LDL, and HDL cholesterol and triglycerides increased over 96 weeks of treatment in both groups Figure , but nonAt Week 96, plasminogen, sVCAM, d-dimer, and fibrinogen levels decreased significantly from baseline in the EFV group  while sVCAM and d-dimer decreased significantly from baseline in the FPV/r group   investigated changes in d-dimer, fibrinogen, or plasminogen. However, data from observational cohorts support similar trends for all 3 biomarkers compared with changes observed in this study ,32-35. IA key limitation of this study is that the clinical significance of the biomarker findings is unclear, and the study did not assess the association between the biomarkers and more clinical evidence of endothelial dysfunction such as changes of flow-mediated dilation ,37. OtheIn this study of primarily African-Americans and Hispanics patients typically underrepresented in clinical trials, ART initiation with either FPV/r or EFV, in combination with ABC/3TC resulted in high levels of virologic suppression in subjects who continued in the study through 96 weeks, with consistent and favorable decreases in thrombotic activity, as reflected by d-dimer changes, and in endothelial activation, as reflected by sVCAM-1 changes. Except for hs-CRP, concentrations of other biomarkers generally remained stable or declined overall, with statistically significant declines observed in plasminogen and fibrinogen in the EFV group. Our study adds to the emerging data that some biomarkers are decreased with ARV therapy and control of HIV viremia. Additional studies are needed to further clarify the clinical significance of these findings and further elucidate whether biomarkers can be used for risk stratification in identifying patients that most benefit from aggressive management of CVD risk.Princy Kumar, MD, has received consulting fees from Bristol-Myers Squibb. She has served on speakers’ bureaus for Boehringer Ingelheim, GlaxoSmithKline, Tibotec Pharmaceuticals, and ViiV HealthCare and has received research funding from GlaxoSmithKline, Merck, and Tibotec Pharmaceuticals.Edwin DeJesus, MD, has received consulting fees from and served on speakers’ bureaus for Gilead Sciences, Merck, and Tibotec Pharmaceuticals. He has received research funding from Abbott Laboratories, Achillion, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffman LaRoche Laboratories, Merck, Pfizer, Schering Plough, Taimed, Tobira, Tibotec Pharmaceuticals, and Vertex Pharmaceuticals.Gregory Huhn, MD, has received consulting fees from GlaxoSmithKline, Gilead Sciences, Vertex Pharmaceuticals, and Tibotec Pharmaceuticals. He has served on speakers’ bureaus for Genentech, GlaxoSmithKline, Gilead Sciences, Merck, Novartis, Sanofi Pasteur, Tibotec Pharmaceuticals, and ViiV HealthCare and has received research funding from GlaxoSmithKline, Gilead Sciences, Merck, Tibotec Pharmaceuticals, and Vertex Pharmaceuticals.Louis Sloan, MD, has received consulting fees from, served on speakers’ bureaus for, and received research funding from ViiV Healthcare.Catherine Butkus Small, MD, has received consulting fees from Schering-Plough. She has received research funding from Abbott Laboratories, GlaxoSmithKline, Pfizer, Schering-Plough, and ViiV Healthcare.Howard Edelstein, MD, has received consulting fees from Gilead Sciences. He has received research funding from Bristol-Myers Squibb, Gilead Sciences, Pfizer, and ViiV Healthcare.Franco Felizarta, MD, has received consulting fees from Merck and Gilead Sciences. He has served on speakers’ bureaus for and has received research funding from Boehringer Ingelheim, GlaxoSmithKline, Merck, Pfizer, Tibotec Pharmaceuticals, and ViiV Healthcare.Ritche Hao, MD, has received consulting fees from Gilead Sciences. He has received research funding from GlaxoSmithKline, Gilead Sciences, Merck, Napo Pharmaceuticals, Merck, Tibotec Pharmaceuticals, and ViiV Healthcare.Lisa Ross, Britt Stancil, Keith Pappa, PharmD, and Belinda Ha, PhD, are employees of GlaxoSmithKline and ViiV Healthcare.PK contributed to the design of this study. PK, ED, GH, LS, CS, HE, FF, and RH enrolled patients in this study. PK and BH were involved in drafting this manuscript, LR and BS contributed to data analysis, and all authors provided critical review of the manuscript and approved it for publication.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/13/269/prepub


The British HIV Association (BHIVA) 2012 guidelines for the treatment of HIV recommend patients start combination antiretroviral therapy (ART) containing tenofovir and emtricitabine as the nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone. BHIVA third agent preferred choices comprise efavirenz, boosted atazanavir, boosted darunavir and raltegravir, and the guidelines further state that ‘fixed dose combinations (FDC) of drugs can increase adherence’ [


Recent studies have suggested that statins possess diverse immune modulatory and anti-inflammatory properties. As statins might attenuate inflammation, statin therapy has been hypothesized to reduce mortality in HIV-infected individuals. We therefore used a Danish nationwide cohort of HIV-infected individuals to estimate the impact of statin use on mortality before and after a diagnosis of cardiovascular disease, chronic kidney disease or diabetes.We identified all Danish HIV-infected individuals  who initiated HAART after 1 January 1998, and achieved virological suppression within 180 days. Date of first redemption of a prescription of statin was obtained from the Danish National Prescription Registry. We used Poisson regression analysis to assess adjusted mortality rate ratios (aMRR). First, time was censored at date of virological failure (VL >500 copies/ml). Second, time was not censored at virological failure. All analyses were adjusted for potential confounders.In the analyses confined to observation time without virological failure (+ censoring) statin therapy was associated with a non-statistically significant reduced rate of death . No difference was observed in the analysis with no censoring . Use of statin seemed to reduce mortality in individuals after a diagnosis of comorbidity {, }. No difference in rate of death could be detected before first date of diagnosis of comorbidity {, }.Statin therapy might reduce all-cause mortality in HIV-infected individuals, but the impact on individuals with no comorbidity seems small or absent. An unambiguous proof of a causal relation can only be obtained in a randomized controlled trial, but the sample size predicted may be prohibitive for its conduct. HMG CoA Reductase Inhibitors (statins) are cholesterol-lowering drugs used extensively in the primary and secondary prevention of cardiovascular disease It is well established by several large clinical trials Recently the potential role of statins in HIV infection has also been subject of a debate. Despite successful suppression of HIV-replication with highly active antiretroviral therapy (HAART), HIV-infected individuals may have persistent inflammation, which can lead to a higher risk of age-associated non-AIDS morbidity As of 1 January 2010 Denmark had a population of 5.5 million, with an estimated HIV prevalence of 0.1% among adults We used the unique 10-digit civil registration number assigned to all individuals in Denmark at birth or upon immigration to link data from the following registers:DHCS, which has been described in detail elsewhere DCRS, established in 1968, is a national registry which stores information on vital status, residency, and migration for all Danish residents International Classification of Diseases [8th revision (ICD-8) until December 31 1993 and 10th revision (ICD-10) thereafter] DNHR, established in 1977, records data on all patients discharged from non-psychiatric hospitals in Denmark. Diagnoses are coded according to the DNPR, established in 1994 by the Danish Medicines Agency at the National Board of Health The study period was 1 January 1998 through 31 December 2009.From DHCS we included all Danish HIV positive patients older than 16 years at HIV diagnosis, who started HAART on 1 January 1998 or thereafter and before 31 December 2009, and within 6 months of that date had an undetectable VL (<50 copies/ml). Individuals who immigrated to Denmark after HAART initiation were excluded . The indThe primary outcome was time to death from any cause as registered in the Danish Civil Registration System (DCRS).Date of first redemption of a prescription of a statin was included as a time-updated covariate. The following statins were included in the analysis: simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin and a combination of the drugs simvastatin and ezetimibe : C10AA01-07, C10BA02). Statins are reimbursable and only available on prescription in Denmark. They are used according to national guidelines We first introduced the following covariates to control for potential confounding (adjustment 1): age , gender, race (Caucasian/non-Caucasian), HIV-transmission group (men who have sex with men (MSM), heterosexual contacts, intravenous drug abuse (IDU), other), hepatitis C status (HCV – defined as being seropositive for HCV and/or having a positive HCV RNA registered in DHCS), calendar year of HAART initiation (<2004 vs. > = 2004), one or more AIDS defining illnesses prior to HAART (yes/no), ART use before initiating HAART, CD4 cell count within +/−1 year of HAART initiation , HIV viral load (VL) +/−1 year of HAART initiation (log10(VL copies/ml)) and a cholesterol level before or up to 1 year after HAART initiation . We further used an extended model (adjustment 2) in which comorbidity and the interaction term between statin use/non-use and comorbidity was also included. In these analyses comorbidity was defined as the date an individual was first diagnosed with one of the following comorbid conditions ) as defined in DNHR and DNPR, and introduced as time-updated variable. ICD8, ICD10 and ATC codes are provided in We computed time from HAART initiation until date of death from any cause, emigration, lost to follow up or 31 December 2009, whichever occurred first. SPSS version 19.0  and STATA software, version 11.0  were used for data analyses. Data from DNHR and DNPR was obtained with approval from the Danish Registry Board. The study was approved by the Danish Data Protection Agency (record number 2008-41-1781).In model A, 145 (8.3%) HIV-infected individuals initiated a statin of whom 124 (7.1%) were started after HAART initiation. These analyses gave rise to a total of 7,952 person-years of follow-up (PYR). Of these 7,528 PYR were before and 424 PYR after statin initiation. In total 109 (6.3%) individuals died of which 7 (6.4%) had initiated a statin drug prior to death. In Model B 169 (9.7%) individuals initiated a statin (148 (8.5%) after HAART initiation) and had a total of 9,865 PYR . 171 HIV-infected individuals died, of whom 15 had initiated a statin. Additional characteristics of the HIV-infected individuals are provided in In the analysis confined to observation time without virological failure (model A1) we found an aMRR of 0.75 (95% CI: 0.33–1.68) for the time after versus the time before or with no initiation of a statin . In the Despite higher rates of comorbidity  in HIV-infected statin users, we observed a trend towards a reduction in all-cause mortality in association with statin therapy in the analyses where patients with virological failure (model A) were censored. In analyses with no censoring (model B), statin users died at the same rate as non-users. Although, use of statin reduced mortality in individuals after a diagnosis of comorbidity the impact on individuals with no comorbidity seemed minimal or absent.The strengths of our study include use of a nationwide population-based cohort with a long observation period and complete follow-up. As we had access to Danish registries of a high quality we could identify all redeemed prescriptions on statins dispensed at Danish community pharmacies as well as valid data on date of death. Furthermore, the availability of electronically collected data on VL, CD4 cell counts and history of antiretroviral treatment from DHCS, minimized potential selection and information bias. As the main aim of the study was to investigate whether we could confirm the findings by Moore et al. Our study has some limitations. We did not consider the specific type of statin therapy or the degree of exposure (dosage and duration), thus assuming that statin-associated benefits were a class effect. However, as statins possess different potencies for HMG CoA reductase inhibition, due to differences in tissue permeability and metabolism this could lead to differences between studies. We analyzed the redemption of prescriptions of statins given the assumption that drug acquisition was a reasonable surrogate for consumption. However, adherence problems might exist. Furthermore, we did not consider cessations or changes of either statin or HAART. In the multivariate analyses we included the baseline CD4 cell count, viral load and cholesterol level; however, we are aware that the absence of the dynamic of these parameters on HAART could have affected the results. Furthermore, as we had no dynamic data on high-density lipoprotein, smoking status, body mass index or blood pressure, we could not adjust for these potential confounders. Due to the study design, we had to rely on hospital registry-based discharge diagnoses in order to identify comorbidity. Importantly, we used the same source of data to ascertain comorbidity for all study subjects. As registration of diagnoses is restricted to hospital contacts, we used first date of redemption of an antidiabetic drug as a surrogate marker of diabetes, as ICD codes are not valid for identification of diabetes. If individuals under study are unlikely to obtain the prescribed medication from sources not captured by the database, the measure can be considered to have a high specificity In a recent study Moore et al. th Conference on Retroviruses and opportunistic infections (CROI), 2011, Overton et al. reported reduced risk of the composite endpoint serious non-AIDS events/death  and malignancies  in patients who were treated with statin.In an unpublished ACTG study, presented at the 19The reduced mortality after statin initiation found by Moore et al. In a large meta-analysis of 14 RCTs of statin effects  Given the observational study design, an RCT of an appropriate size is needed to achieve a valid evaluation of statin effects on mortality in HIV-infected individuals. However, using the mortality rates seen in our study, more than 25.000 patients have to be recruited into each arm in an RCT to detect a 10% reduction in mortality with 3 years of follow-up . Statins are already widely used and although these drugs are rather safe and tolerable, 3 recent meta-analyses In conclusion, statin therapy might have a beneficial effect on all-cause mortality in HIV-infected individuals, but the impact in individuals with no cardiovascular disease, chronic kidney disease or diabetes is small or absent. An RCT is needed to make an evidence-based proof of a causal relation. However, as patients with high risks of cardiovascular disease obviously cannot be included in the trial, the sample size needed may be prohibitive for the conduct of the study.Appendix S1ATC codes of cholesterol reducing drugs.(DOC)Click here for additional data file.Appendix S2Diagnostic codes of comorbidity (ICD 8 and ICD 10 codes).(DOC)Click here for additional data file.Appendix S3ATC codes of antidiabetic drugs.(DOC)Click here for additional data file.


HIV-infected prisoners lose viral suppression within the 12 weeks after release to the community. This prospective study evaluates the use of buprenorphine/naloxone (BPN/NLX) as a method to reduce relapse to opioid use and sustain viral suppression among released HIV-infected prisoners meeting criteria for opioid dependence (OD).From 2005–2010, 94 subjects meeting DSM-IV criteria for OD were recruited from a 24-week prospective trial of directly administered antiretroviral therapy (DAART) for released HIV-infected prisoners; 50 (53%) selected BPN/NLX and were eligible to receive it for 6 months; the remaining 44 (47%) selected no BPN/NLX therapy. Maximum viral suppression (MVS), defined as HIV-1 RNA<50 copies/mL, was compared for the BPN/NLX and non-BPN/NLX (N = 44) groups.The two groups were similar, except the BPN/NLX group was significantly more likely to be Hispanic (56.0% v 20.4%), from Hartford (74.4% v 47.7%) and have higher mean global health quality of life indicator scores (54.18 v 51.40). MVS after 24 weeks of being released was statistically correlated with 24-week retention on BPN/NLX [AOR = 5.37 ], having MVS at the time of prison-release [AOR = 10.5 ] and negatively with being Black [AOR = 0.13 ]. Receiving DAART or methadone did not correlate with MVS.In recognition that OD is a chronic relapsing disease, strategies that initiate and retain HIV-infected prisoners with OD on BPN/NLX is an important strategy for improving HIV treatment outcomes as a community transition strategy. Combination antiretroviral therapy (cART) has markedly reduced morbidity and mortality from HIV disease. Individuals with HIV disease transitioning to the community from the criminal justice system (CJS) are a particularly vulnerable population where effective interventions are urgently needed. Reasons for poor post-release outcomes among PLWHA are complex and multifactoral, Despite evidence to support successful treatment for opioid dependence using opioid substitution treatment (OST) in community and CJS settings, (e.g. methadone and buprenorphine), The rationale and description of the overall prospective study of directly administered antiretroviral therapy (DAART) has been describe Eligible subjects were recruited during the years 2005–2010 from among 154 HIV-infected prisoners transitioning to the community enrolled in a randomized controlled trial (RCT) of directly administered antiretroviral therapy (DAART). Within 90 days before community-release, all subjects underwent informed consent, baseline assessments and chart review. Assessments included demographic information, mental illness and chemical dependence screening using the Mini-International Neuropsychiatric Interview (M.I.N.I), www.clinicaltrials.gov (NCT00786396). Additional assurances to protect the participants were obtained from the Office of Human Research Protection (OHRP) at the Department of Health and Human Services, and a Certificate of Confidentiality from the National Institutes of Health was also obtained. As mentioned above, written consent to participate in the parent trial The Yale University Human Investigation Committee and the Connecticut Department of Correction Research Advisory Committee approved this study and the parent study is registered at BPN/NLX induction and maintenance procedures have been described previously, BMT was defined as having received even a single dose of BPN/NLX along with weekly, standardized and manual-based counseling per protocol Subjects receiving BMT were evaluated daily by the study clinician during the induction phase and at least monthly thereafter. Counselors met with subjects weekly, irrespective of study assignment, and assessed urine toxicology screening, opioid craving, BPN/NLX satisfaction and adverse side effects. Structured interviews and phlebotomy for CD4 lymphocyte count and HIV-1 RNA level were conducted at weeks 4,12 and 24 after release.P-values censored at ≤0.20 were restricted to enter and leave the model. Aikake (AIC) and Bayesian Information Criterion were applied to each model to assess goodness of fit and to avoid over fitting of data. Missing HIV-1 RNA values were considered as failures (HIV-1 RNA >50 copies/mL).All statistical analyses were conducted using STATA v.10 . Outcomes from the first 24 weeks are reported for all 94 subjects meeting DSM-IV criteria for opioid dependence who were including in the parent RCT. The primary outcome was defined as the proportion of patients achieving maximal virological suppression (MVS), or HIV-1 RNA <50 copies/mL, at 24 weeks. Using logistic regression analyses, univariate analysis was performed to assess the impact of potential independent variables associated with the primary outcome. Subsequently, a multivariate model was fitted to the data, using both backward and forward stepwise regression approaches incorporating Bonferroni correction; Among the 94 participants who met pre-incarceration DSM-IV criteria for opioid dependence, we sought to conduct a naturalistic study comparing those who initiated buprenorphine maintenance treatment (BMT) with those who did not. Those not initiating BMT included those that selected either methadone maintenance therapy  or no OST (N = 35). Because of the naturalistic nature of the follow-up, those not receiving BMT received what is routinely available as standard of care in community settings for those receiving MMT and no OST (including available counseling).The independent substance abuse variables of interest were: 24-week retention in BPN/NLX treatment and degree of addiction severity using the Addiction Severity Index (ASI). Non-BPN group (n = 44), the BPN group not retained for 24 weeks (n = 33) and the BPN group of subjects who were retained for the full 24 weeks (n = 17). There was no statistically significant difference for mean CD4 count over the 6 months between the three groups (p = 0.38) nor was there for the percentage having a VL <400 copies/mL (p = 0.08). There was, however, a statistically significantly greater percentage of the BPN group who were retained for 24 weeks group having MVS over the 6 months when compared to the Non-BPN and the BPN and not Retained for 24 Weeks group (p = 0.01).To our knowledge, this is the largest longitudinal follow-up of HIV-infected prisoners on antiretroviral therapy and meeting pre-incarceration DSM-IV criteria for opioid dependence. The findings from this study have several important implications as described below.First, being retained on BPN/NLX, along with standardized counseling recommended for HIV-infected patients on BMT, was superior in sustaining maximal viral suppression compared to those not receiving BPN/NLX. This remained true in this naturalistic study where participants could choose their own post-release treatment options, even when controlling for receipt of other OST, including methadone. Unlike our previous pilot BPN/NLX study, we not only examined participants for a longer treatment duration (24 weeks), but also were able to compare outcomes to other opioid dependent participants who did not receive BPN/NLX, including those opting for methadone.Second, the finding that retention on BMT, along with related counseling and follow-up, was strongly and significantly correlated with MVS confirms findings from other studies where integrating BPN/NLX into HIV clinical care settings is independently associated with viral suppression. Third, though the DAART intervention was superior to SAT in the parent trial, it was not independently associated with MVS among these opioid dependent subjects. Fourth, craving for opioids is associated with a high rate of opioid relapse among those who have undergone supervised opioid withdrawal. enhanced treatment as prevention’. The extent to which CJS administrators, public health officials and public policy makers adopt BPN/NLX, or any effective MAT for that matter, remains problematic in that such evidence-based interventions are generally not available to CJS populations in the U.S. Integrating BPN/NLX with cART for released OD prisoners has significant public health implications. Suppression of HIV replication will ultimately contribute to decreases in transmission of HIV to the uninfected public. ART alone has been found to reduce spread of HIV infection to serodiscordant couples International guidelines have recently been published that support the use of methadone in HIV-infected patients receiving cART, DAART for released prisoners and the integration of DAART into methadone treatment in community settings. There are limitations to this study including the relatively small sample size and single study site. Receipt of BPN/NLX was not randomized, therefore potentially introducing selection bias. For example, those selecting BMT may have been more motivated to receive treatment in order to avoid relapse to opioid use. This increased motivation may have influenced adherence to BMT compared to those not selecting BMT. It is clear, however, that this analytic approach represents a real-world sample and reflects the realities of what individuals seek as treatment options. Moreover, it is clear that those selecting BPN/NLX were not just selecting it over methadone because it might provide more freedom in their day to day life, since two thirds of BPN/NLX participants received their BMT daily as observed therapy by virtue of being in the DAART arm. Though future studies should consider deploying a randomized controlled trial (RCT) design to eliminate the possibility of such selection bias, such an approach will not overcome concerns about inclusion of patient preferences since it is unlikely that such a RCT could ever realistically be conducted as placebo-controlled. Additionally, though we know the extent of the counseling provided to the BMT group, the Non-BPN comparison group was not followed as closely and did not include urine toxicology testing. Though counseling has been demonstrated to enhance the benefits of OST, counseling alone would be entirely insufficient to provide significant benefit. In conclusion, buprenorphine induction upon release for HIV-infected opioid dependent prisoners is highly acceptable and feasible. Retention on buprenorphine, irrespective of other medical or psychiatric comorbidity, evidence-based adherence interventions or use of methadone, was strongly associated with maximal viral suppression. Buprenorphine maintenance treatment, along with concomitant counseling, effectively enhances the benefit of cART as enhanced treatment as prevention for released HIV-infected opioid dependent prisoners and has great potential to improve health from an individual and public perspective.


The study aimed to determine the cost impacts of antiretroviral drugs by analysing a long-term follow-up of direct costs for combined antiretroviral therapy, cART,-regimens in the nationwide long-term observational multi-centre German HIV ClinSurv Cohort. The second aim was to develop potential cost saving strategies by modelling different treatment scenarios.Antiretroviral regimens (ART) from 10,190 HIV-infected patients from 11 participating ClinSurv study centres have been investigated since 1996. Biannual data cART,-initiation, cART-changes, surrogate markers, clinical events and the Centre of Disease Control- (CDC)-stage of HIV disease are reported. Treatment duration was calculated on a daily basis via the documented dates for the beginning and end of each antiretroviral drug treatment. Prices were calculated for each individual regimen based on actual office sales prices of the branded pharmaceuticals distributed by the license holder including German taxes.During the 13-year follow-up period, 21,387,427 treatment days were covered. Cumulative direct costs for antiretroviral drugs of €812,877,356 were determined according to an average of €42.08 per day (€7.52 to € 217.70). Since cART is widely used in Germany, the costs for an entire regimen increased by 13.5%. Regimens are more expensive in the advanced stages of HIV disease. The potential for cost savings was calculated using non-nucleotide-reverse-transcriptase-inhibitor, NNRTI, more frequently instead of ritonavir-boosted protease inhibitor, PI/r, in first line therapy. This calculation revealed cumulative savings of 10.9% to 19.8% of daily treatment costs . Substituting certain branded drugs by generic drugs showed potential cost savings of between 1.6% and 31.8%.Analysis of the data of this nationwide study reflects disease-specific health services research and will give insights into the cost impacts of antiretroviral therapy, and might allow a more rational allocation of resources within the German health care system. The implementation of combined antiretroviral therapy, cART, as the standard of care since the middle 1990s has substantially reduced morbidity and mortality in HIV-infected individuals The regulation of pricing and the reimbursement of prescription medicines vary considerably between different countries and result in notable differences in the market prices of medicinal products In Germany, the yearly direct costs of HIV disease to the health care system were estimated as €24,482 per patient in 2001 Market prices for pharmaceuticals can be calculated by the manufacturer without negotiation with the authorities or health care insurers.Until recently, health economic aspects were hardly considered by the German guidelines for antiretroviral treatment.Several health care reforms have recently been implemented in Germany to restrict the increasing expenditure. Equity and effectiveness should be enhanced by reimbursements that are calculated on the basis of lump sums for hospital stays (German disease related groups: G-DRG) and within the German risk structure compensation for health care insurance.economic efficiency principle by the German Social Insurance Code, when they choose treatment alternatives for patients within the statutory health insurance fund: “Services must be sufficient, appropriate, and cost-effective; they must not go beyond the indispensable minimum” In Germany physicians are obligated to the The knowledge on the impact of the use of antiretroviral treatment on direct costs within the German health care system is scarce st 1999.By law  the Federal Commissioner for Data Protection and Freedom of Information recommended the clinical surveillance of HIV-infection in Germany. The Clinical Surveillance of HIV Disease, ClinSurv study, was approved by the Federal Commissioner for Data Protection and Freedom of Information. No personal data and no biomaterials are collected. The Federal Commissioner for Data Protection and Freedom of Information waived the need for written consent, because data are reported anonymously to the German Public Health Institute, the Robert Koch-Institute. The ClinSurv study is an ongoing, prospective, long-term observational cohort study. The study design is described in detail elsewhere Due to the fact that the cohort enrolment was initiated in the pre-cART era, patients on single-drug cART or double-combination cART, as well as patients on cART, were included in the cohort. A biannual data collection was performed using local electronic databases that capture information on antiretroviral therapy, treatment initiation and changes in treatment since the first visit to the reporting centres. Immunologic, virologic and demographic data, AIDS-defining diagnoses and information on cART are reported. All time-related variables were collected and referenced according to their days of occurrence. The data were validated and monitored manually as well as electronically at the coordinating centre. The source data were verified and double reporting was excluded.The history of antiretroviral therapy administration was documented individually by beginning and end dates and the administered dosages were calculated on a daily basis for every single antiretroviral drug. The active substances in each particular pharmaceutical ingredient are categorized by their International Non-proprietary Names (INN). All INN were categorized within their appropriate substance classes, which are defined by their mode of action . In addiTreatment entities are defined as substance regimen (SR) by lists of pharmaceutical ingredients or as class regimen (CR) by the list of their dedicated substance classes for all individual antiretrovirals taken at the same time. The amounts of all single drugs and the numbers of antiretrovirals representative for each single substance class were calculated and defined as the daily swallowed pill burden. The regimens were defined as PI-boosted if ritonavir was added to another PI in a daily dose of less than or equal to 400 mg per day, whereas ritonavir was regarded as an antiretroviral active drug when given in a higher dosage. In order to assign an individually appropriate treatment line, the cART history was retrospectively documented in all patients who started cART before entering the study. Any qualitative change of treatment regimen defined a subsequent regimen and via this an incrementally increasing treatment line. If it was known that a patient was treatment naive, a regimen was defined as the first line regimen. Treatment naive patients were not included in the cost analysis unless at the point of initiation. Treatment interruption was defined as any period without the intake of cART by a previously treated patient.www.lauer-fischer.de). No direct costs were assigned for particular antiretroviral substances during periods of early access programmes before licensing of the drug in Germany. Treatment costs were calculated exclusively for the days under treatment with at least one antiretroviral drug, including hydroxyurea, which was assumed to have antiretroviral effects in the late 1990s. The potential impact of discarded drugs when regimens were changed and when non-adherence (e.g. forgotten doses) was reported were not included in the cost analysis. The mean costs over time were adjusted for the annual German consumer price indices . The German national annual increments of the consumer price index in percentages were: 1996: 1.4%, 1997: 1.9%; 1998: 1.0%; 1999: 0.6%; 2000: 1.4%; 2001: 1.9%; 2002: 1.5%; 2003: 1.0%; 2004: 1.7%; 2005: 1.5%; 2006: 1.6%; 2007: 2.3%; 2008: 2.6%.Allocation of direct costs for cART was calculated by daily standard doses for all elements of an entire regimen (treatment days) on the basis of historical and actual office sales prices of the original pharmaceuticals distributed by the license holder; the prices include German taxes as given in the German pharmaceutical online database  by NNRTI in first line therapy were calculated. Assuming that in the near future generic zidovudine, lamivudine, nevirapine and efavirenz will be available in Germany, the potential cost impact of using these generic drugs was modelled. Scenarios with a price reduction between 20% and 90%, as compared to the recent prices for branded drugs, and prescription rates of 20% up to 90% for applicable generic drugs were calculated. For the purposes of this analysis it was also assumed that branded emtricitabine could be substituted by generic lamivudine in certain cases.Quarterly datasets were determined for the observation period. Statistical analysis was performed using PASW 18 statistical software. Mean values and their standard deviations were calculated. Differences between the means were compared by ANOVA tests. The p-values of <0.05 were considered as denoting statistical significance, and all tests of significance were two-sided.st 1996 to December 31st 2008. Nearly 80% of these patients were male, 75% were German born, and over 60% were symptomatic according to CDC-B and CDC-C classification . Each regimen was comprised of 3.4 substances (mean +/−0.79), including ritonavir. Ritonavir appeared in 33% of all regimens prescribed. The regimens with boosted PI/r contained significantly more antiretroviral components (4.2+/−0.65) and ARV classes (2.07+/−0.39) than non-boosted regimens  of PI/r-based treatment regimens was reported in the entire cohort . When analysing patients exclusively on their first line treatments , PI based regimens (52.3%) predominate as well NNRTI-based regimens, but NNRTI outweigh the P based regimens in second-  and third-line regimens . NNRTIs were available later than PI, and therefore the use of NNRTI increased over time in early treatment lines. In 1998: 12.7% in first, 14.6% in second, and 12.1% in third line treatment as compared to 51.2%, 58.9% and 54.2% in 2008. Until 2001, virtually all regimens consistently contained one or more nRTIs. In contrast, in later treatment, the lines that switched from NNRTI to PI/r prevailed.The proportion of more recently licensed drug classes  was cumulatively less than 5% among all of the ARV regimens reported in 2008, with a tendency to increase. Overall, 2.2 different single antiretroviral substance regimens were prescribed in the cohort and 197 different drug class regimens  were comUp to 48 treatment lines were documented within the observation period. The means and maximums of treatment lines increased during the 13 year follow-up period. The proportion of patients who received a first line regimen was highest at the start of the observation period in 1996 (39.6%) and lowest in 2008 21.6%; .Between 1996 and 1999 the mean daily drug costs for an entire regimen increased substantially (+72%: €21.89+/−9.57 to €37.70+/−9.21) by the introduction of triple c-ART. Since 1999 the increase in daily drug costs was more moderate until 2008 (33%: € 50.05+/−16.47). As a consequence of a 16% price cut enacted by law, a sharp decline of 15.4% was observed between 2003 (€45.82) and 2004 (€38.75). After adjusting costs for the annual German consumer price indices , the real increase in daily drug prices for the prescribed cART regimen in the cohort was 13.5%  increased substantially in advanced treatment lines, but remained constant for nRTI, and decreased for NNRTI .In symptomatic HIV-disease stages the mean daily drug costs for cART were higher  compared to patients with asymptomatic or unknown stages of HIV . Differences were less pronounced than those between treatment regimen lines, reflecting the fact that complex treatment histories were also seen in less advanced stages of the disease.The direct costs of cART were lower for females (€40.42+/−12.65) than males . The amount of daily swallowed pills (pill burden) decreased via the incremental use of fixed drug combinations from 11.02 bits/day (+/−5.11) in 1998 to 4.53 bits/day (+/−2.63) in 2008. In parallel, the proportion of regimens with three or fewer pills per day increased from 5.6% to 41.1% in 2008, hence the price per bit increased substantially from €3.38 to €14.22 per day during that time .Overall, 4.9 million out of 19.4 million treatment days in this cohort (25.3%) referred to patients receiving first line therapy. The proportions of NNRTI- and PI-comprising first line regimens were comparable . In contrast, the mean daily costs of the PI/r regimen were higher than the costs of NNRTI-comprising regimens . Hypothetically, assuming that at least 50% and as much as 90% of a PI/r-comprising first line regimen could be substituted by less expensive NNRTIs, this change would result in cumulative savings of 10.9% to 19.8% respectively, of the daily treatment costs.Of all of the direct costs of antiretroviral drugs, 44.4% are related to the use of zidovudine, lamivudine, emtricitabine, nevirapine and efavirenz, which were exclusively available as branded drugs within the observation period. These drugs might be candidates for substitution by generic drugs or equivalents in the near future in Germany. The relative cost impact of these potentially replaceable branded drugs decreased from 44.1% in 2005 to 34.9% in 2008 for all of the mean direct costs of antiretrovirals .Using different hypothetical price cuts related to the use of generic drugs (from 20% up to 90% as compared to recent prices of the branded drugs) and different rates of substitution of the branded ARVs by generics (20% to 90%), the potential impact for cost savings was calculated as ranging from 1.6% up to 31.8% of the direct costs of all prescribed antiretrovirals  and for drugs only available on prescription Cost analyses take the cost-bearer's view and therefore the costs of antiretrovirals given in clinical trials or expanded access programmes are disregarded. Thus, the monetary assessment of cART in this study should almost exclusively reflect the antiretroviral regimens in clinical day life, which should be geared towards current national treatment guidelines Within a clinical setting there might be a need to change an antiretroviral regimen due to several reasons, which can result in a rather short median duration of first line regimens of a couple of months Variations and clusters of certain regimens between participating centres were obviously determined by on-going studies or by the pre-selection of patients with particular co-morbidities or more advanced stages of HIV at some of the ClinSurv centres. For example, boosted double PI-regimens were not recommended by German treatment guidelines but they still accounted for a 1.0% of all documented regimens within the cohort. These patients predominantly presented at particular study centres.Treatment recommendations from the treatment guidelines reflected rather data regarding efficacy and tolerability from clinical trials than health and economic considerations Regarding the statutory German efficiency principle for drug prescription it is noteworthy that in the cohort study the proportion of NNRTI-based cART increased rapidly at the end of the 1990s , resultiNucleoside/nucleotide analogues were used as the backbone of virtually all regimens during the whole observation period. However, the proportion of nRTI-sparing regimens increased with the availability of new drug classes from 2003 and remained at more than 1% until 2008 . Within From 2003, newly licensed antiretroviral drug classes  became available. They were primarily licensed for use in treatment-experienced patients exclusively. Cumulatively, these new drugs accounted for less than 5% of ARV-regimens in 2008, but with an increasing tendency . Virtualwww.destatis.de; 1996 = 100%), the real increase in daily drug prices for the prescribed cART regimens in the cohort was 13.5% within the studied 10-year period . In 2010, the insurers retrieved a Morbi-RSA of €18,455.18 per year and capita for each HIV-infected patient receiving antiretroviral therapy. This study found that the HIV-specific Morbi-RSA nearly exactly covered the calculated mean costs of ARV regimens  in 2008. However, drug prices have risen since 2008 and a lump sum, which exclusively covers the direct costs of cART, does not cover the direct costs of concomitant drug therapy, hospitalization or regular check-ups and therefore might indicate an underfunding for people living with HIV and AIDS (PLWHA) by the Morbi-RSA. This could cause discrimination, especially of PLWHA in the advanced stages of HIV within the German health care system in the future, especially if the Morbi-RSA is not adapted adequately. Analysis of data from German health insurance companies potentially underestimates the cost impact of cART in PLWHA. Insurance databases include a significant proportion of single prescriptions of antiretroviral drugs, presumably for post-exposure prophylaxis www.emea.com). After that third party suppliers are allowed to claim a license for a chemically identical drug.. All generic drugs approved by the EMEA and FDA have the same high quality of ingredients, strength, purity and stability as brand-name drugs. Generic drug manufacturers must show that a generic drug is bioequivalent to the brand-name drug, which means the generic version delivers the same amount of active ingredients into a patient's bloodstream in the same amount of time as the brand-name drug. They must have the same dosage form  and must be administered in the same way. Generic drug labelling must be essentially the same and generic drug manufacturers must fully document the generic drug's chemistry, manufacturing steps and quality control measures. Moreover, the generic manufacturing, packaging, and testing sites must pass the same quality standards as those of brand name drugs . As for all medicines, the safety of generic medicines continues to be monitored after authorisation. Each company is required to set up systems to monitor the safety of all medicines that it markets. Regulatory authorities may also perform an inspection of these monitoring systems. If specific safety precautions have to be considered when taking the reference medicine, the same precautions will generally also be required for the generic medicine .Patent protection allows the license holder exclusive marketing and price negotiations for a defined time period after the approval of a new drug and this is regulated by national and international laws. Product licences for the treatment of HIV/AIDS, cancer and neurodegenerative diseases will have a longer period of exclusivity compared to other drugs due to different approval systems in the EU .Until recently, all antiretroviral drugs in Germany were protected by patents and were exclusively available as branded labels. However, patent protection for zidovudine (AZT) and lamivudine (3TC) has recently expired and it will expire for nevirapine (NVP) and efavirenz (EFV) in the near future. In 2010, 3TC became available as a generic drug within the European Union (EU) exclusively. In Spain, price reductions of up to 55% can be found compared to branded 3TC (PMFarma 2010; Generics are able to induce substantial price reductions for pharmaceuticals. The impact of antiretroviral generics on the direct costs of cART depends on the willingness to prescribe them broadly Assuming that generic drugs will become widely available and will have an equivalent bioavailability and tolerability as branded drugs, a high penetration of the market segment will possibly be achieved. In addition with the availability of generic lamivudine, an economically based substitution of emtricitabine by generic lamivudine might also occur. The cytidine analogues emtricitabine and lamivudine have a similar resistance profile However, some disadvantages may arise by the introduction of generic drugs. There might be an increase in the pill burden caused by the unbundling of branded co-formulations. This might influence the adherence of patients. Although there is evidence that a high pill burden, a high frequency of dosing or both inversely correlate with patient adherence, there is little evidence for a certain threshold in the number of items swallowed daily or an advantage of the administration frequency as long as it is below three times per day. Therefore, it remains more crucial to find an individually tolerable drug combination than to minimize the pill burden Assuming that the number of PLWHA in Germany will increase and as recent guidelines recommend treatment at earlier stages of asymptomatic HIV infection and at CD4+ T cell counts of less than 500/µl, many more patients will receive cART in the future. The German nationwide potential for annual cost savings by choosing economically priced antiretroviral regimens could increase up to more than 500 million euros per annum within the next few years. But this goal will be hard to achieve. Even if patients and physicians could be incentivized to consider economically alternative regimens, they will often choose a more expensive alternative Choosing economical alternatives in antiretroviral treatment does not necessarily mean that the pharmaceutical industry will lose earnings and market share in the future.The development of new innovative antiretroviral co-formulations will be simplified by the availability of generic antiretroviral drugs.. This could result in advantageous treatment options for the patients. By this way, license holders of still branded antiretroviral drugs would get the opportunity to improve their portfolio and to increase their sales volume and profits.Cost calculations from a representative, disease-specific clinical cohort, like ClinSurv, could have an impact on future cost savings. This approach would allow future definition of the cost impacts of particular subgroup treatments, for example patients in progressed stages of treatment, more precisely for the health care system and its stakeholders. In addition, it would allow the cost impacts of evolutionary changes in treatment guidelines and transitions within the German health care system to be evaluated in a prospective manner The market for antretroviral drugs in the world is subdivided into at least three parts: By international policies, funding, gradual national prizing, and waiver of license fees by some patent holding pharmaceutical companies in middle- and low-income countries the drug prices vary considerably from those in the high-income countries. As discussed above the data in this study are generated from the German ClinSurv cohort using the nationwide official German pharmacy prices, which are by several reasons in an upper range even compared to other countries with a high per capita gross national product. Therefore data and conclusions from this study can not be generalised to the situation in low- and middle-income countries. Due to several unique characteristics of the German health care system and particular regulatory issues any comparison with other contrastable rich countries should be used cautiously.The study focuses exclusively on direct cost for antiretroviral treatment. Other direct costs of treatment, indirect costs and intangible costs remain disregarded.Updates of treatment guidelines may be of high impact on treatment costs and may reduce the number of potentially cost-saving alternative treatment choices. Such potential effects for the future had not been calculated in the study.The used cohort data may reflect predominantly a real clinical life scenario but do not allow to investigate strategic issues, which would be addressed more accurately in a controlled clinical trial. Basically, there is a need for such trials, especially in the field of health economics. On the other hand policy makers and stakeholders have to deal with existing regulatory issues within the public health system. Beside the description of the recent cost impact of cART the presented study intends to describe a potential short-term economic impact on direct costs, by using generic antiretrovirals in a variable extent Remaining concerns regarding ethical issues to interchange branded antiretroviral drugs with generic antiretroviral drugs can neither be confuted nor confirmed by the study.Drug prices and regulatory issues are specifically taken from the German health care system and a comparison or generalisation of data and conclusions from this study to other health care settings should be performed with caution.


To assess the usefulness of monotherapy with lopinavir/ritonavir (LPV/r) as an option for antiretroviral treatment in clinical practice.Seventy-seven subjects  with HIV-1 RNA <50 copies/mL for at least 6 months, were switched to LPV/r as single antiretroviral agent. Reason for changes were simplification strategy (36.4%) or toxicity (63.6%) either mitochondrial toxicity (55.8%) or other (7.8%). Treatment with LPV/r was maintained for at least 3 months.3 (range 33−1433) and the end of follow-up 634.5 cells/mm3 (range 99−1547), with an increase of 115.6 cells/mm3. In 8 patients, 13 blips were detected , which did not warrant a change in therapy. Differences between patients with and without virological failure during LPV/r monotherapy included: older age at HIV-1 diagnosis , time of undetectable viral load prior to starting monotherapy , and CDC category C . On the other hand, there were no significant differences according to sex, risk group, previous failure to PIs( 9 patients), nadir CD4+ T cell count, or reasons to change to monotherapy. In the Cox regression analysis, age was independently associated with virological failure.The average time from HIV-1 diagnosis to starting HAART was 54 months. Patients had received a median of 7 antiretroviral drugs (range 3-14). The previous antiretroviral regimen included LPV/r in 55 (71.4%) patients. After a mean (±SD) follow-up of 25 (±16) months (median 22 months), viral load remained undetectable in 68 patients (90.7%) , and virological failure was detected in 9 (11.7%), due to poor adherence in 7 (77.8%). The median time of undetectable viral load prior to initiating LPV/r monotherapy was 36 months. The mean CD4+ T cell count at the time of beginning LPV/r was 518.9 cells/mmLPV/r monotherapy has been an effective alternative in clinical practice either as a simplification strategy or in patients in which toxicity reduces the selection of antiretroviral drugs. Poor adherence and greater age were related to a higher rate of therapeutic failure.


National programs are facing challenges of loss to follow-up of people living with HIV/AIDS (PLWHA) on antiretroviral therapy (ART). We sought to identify risk factors associated with early loss to follow-up among HIV-infected patients on ART in Togo and the outcome of such patients.This was a retrospective cross-sectional study using medical records of all patients older than age 15 years enrolled at 28 treatment centers who were on ART programs and who were lost to follow-up from 2008 to 2011.Of the 16,617 patients on ART, 1,216 (7.3%) were lost to follow-up. Most (94.1%) were infected with HIV-1 and 32.6% were in WHO stage III or IV. The median CD4 count was 118/mm3 (IQR: 58-178 cells/mm3). No telephone number was mentioned in the medical records of 212 patients. Of the 1004 patients whose phone number was listed, 802 patients (79.9%) were not reachable on the recorded number, 114 patients (11.4%) were alive and 88 patients (8.8%) had died. In multivariate analysis, factors associated with loss to follow-up during the first 6 months of ART were: age below 35 years , female sex , WHO stage III or IV , existence of an opportunistic infection , and follow-up in a public centre .This study identified several factors associated with lost to follow-up during the first 6 months of ART, and confirmed high mortality among these patients. The National AIDS Program should strengthen medical support of PLWHA in Togo including active case follow-up. Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) are major public health problems in sub-Saharan Africa. Since the introduction of antiretroviral access programs in Togo, significant progress has been noted in the care of people living with HIV (PLWHA). From November 2008, antiretroviral therapy (ART) was provided free of charge to PLWHA while biological monitoring became free in 2010. Since then, the number of PLWHA support centers has increased from 70 in 2008 to 115 in late 2010, scaling-up treatment coverage of antiretroviral therapy from 2% in 2004 to 62.8% in late 2010 [In the framework of scaling up the treatment at the sub-national levels, national programs are facing several challenges including the problem of loss to follow-up of PLWHA following the start of ART in treatment centers –6. The cThis was a retrospective cross-sectional study carried out in 28 centers in Togo prescribing ART . The choice of 28 treatment centers was done by convenience to cover the whole country, and targeted structures with large active patient populations. Indeed, over 80% of PLWHA in Togo are supported in these 28 centers. The study focused on medical records of PLWHA age older than 15 years on ART, who were lost to follow-up between January 2008 and October 2011. This period was selected because ART and biological screening became available for free during 2008 and 2011 was the last year of data available. According to the National AIDS control guidelines, a patient on ART was qualified as lost to follow-up when review of the medical records for the patient did not find evidence that he had died or moved four months after the last visit.Once enrolled in a specific clinic, HIV-infected patients are requested to get all future treatment — provided at no charge — at that same clinic each month. Their contact numbers (if available) and information related to their clinic visits are recorded in their clinic record. To identify the outcome of patients lost to follow-up, study investigators called the patient's telephone number listed in the clinic record or his attendant's telephone number if this existed in the record. Patients were classified into two groups with respect to the time between the beginning of ART and loss of follow-up: early  and late (more than 6 months).Data were collected using a form validated by the Togolese National AIDS Program that had been tested in five clinics in Lomé. Six teams were deployed for data collection. Each team included two medical students who received two days of training on how to review patient's records in the HIV clinics; for each team, the two medical students reviewed the same patients’ records and then the study team reconciled inconsistencies in the information collected by individual abstractorsData were recorded using the software Epi Info version 3.5.1. For continuous variables, medians and interquartile ranges were calculated while for categorical variables we calculated proportions and respective 95% confidence intervals. Our main outcome variable was loss to follow-up at less than or equal to 6 months compared to loss to follow-up at greater than 6 months. The chi-square test or Fisher′s exact test were used when appropriate in bivariate analysis. Multivariate backwards stepwise logistic regression analysis was performed to identify independent risk factors for the dichotomous outcome lost to follow up or not lost to follow up. All variables significant during bivariate analysis at a p-value less than 0.05 and variables previously associated with lost to follow-up were included in the multivariate analysis. However, we excluded CD4 count as this is a component of the World Health Organization stage, and we used the latter as a measure of severity. We then removed variables in a stepwise fashion that were not significant at a p value > 0.1. We also assess for the level of significance of the likelihood ratio of the test. No interaction was identified for variables included in the model. Multivariate logistic regression analyses were performed using the method of MANOVA in Stata 11.This study was approved by the Ministry of Health of Togo's board committee. Reference No 01/2011/MS/DGS/DSSP/PNLS-IST. We obtained verbal consent from study subjects that participated in the phone call.From January 2008 to October 2011, 16,617 patients were placed on ART in the 28 included medical care structures. Among the total of 16,617 PLWHA, 1216 (7.3%) were lost to follow after the initiation of ART. Of these 1216, 290 had early loss to follow-up while 926 had late loss to follow-up. Baseline characteristics of the 1216 patients are summarized in During bivariate analysis, of the 1216 people lost to follow-up, those with early compared to late loss to follow-up were more likely to be under age 35 years , to have had an opportunistic infection at the beginning of ART , to live in a rural area , and to have received treatment in a public structure  .During multivariate analysis, we included variables significant at p < 0.05 on bivariate analysis. Of the 1216 patients, 1119 (93%) had data for all relevant variables and were included in the model. In the model, hemoglobinemia was removed (p = 0.3). The following factors remained significantly associated with early lost to follow up of PLWHA on ART: age below 35 years , female sex , WHO stage III or IV , existence of an opportunistic infection , and follow-up in a public structure  .Among the 1216 patients, no telephone number was mentioned in the medical records of 212 patients and for 802 patients, the listed telephone number did not work. Of the remaining 202 patients, 114 patients (56%) were alive and 88 (44%) had died.This study shows that the factors in Togo associated with early loss to follow of PLWHA on ART are age, gender, WHO stage of disease, existence of an opportunistic infection and type of clinic delivering HIV/AIDS care. Among the subset of patients for whom this information was available, we have demonstrated that a major reason for lost to follow-up is death; it is possible that a major reason we could not contact many people by telephone is because of death, and if this occurred, our mortality estimates will be conservative. In summary, lost to follow-up frequently follows severe disease, including death, and particularly among women and younger adults.The proportion of patients lost to follow reported in Togo was significantly lower than the 13-40% reported by other studies in sub-Saharan Africa . This maThe severity of disease also likely played a role in determining our results. The CD4 count in our study was less than 200 / mm3 for 76% of patients at the beginning of ART with a median count of 119/mm3. Thus, in Togo most patients begin ART once they meet the clinical criteria for AIDS. While this is consistent with other studies from sub-Saharan Africa [In multivariate analysis, five factors  were associated with early loss to follow up of PLWHA on ART. Our study could not determine further why these factors contributed to loss to follow-up. Three of the factors — WHO stage , 13, oppIn our study, 80% of patients whose phone numbers existed in their medical record could not be reached on these numbers. Previous studies have reported values of 35%  and 27% The national STI/HIV/AIDS control program should take these results into account to strengthen the medical support of PLWHA in Togo, targeting young patients, those seeking care in public centers, and those with the most severe disease. For example, community health workers could actively track persons with HIV. Less expensively, health care providers could send SMS text messaging reminders, targeting high risk groups, a method that has worked in other settings , 21. MosAs with many retrospective studies, data were missing from many patients, particularly for information collected during the phone follow-up component. Consequently, we likely did not fully evaluate some important risk factors. Additionally, data may have been incompletely recorded in medical records. This could have affected risk factor data  or outcome data . This is a necessary limitation for our study, where we aimed to determine risk factors for lost to follow-up in actual practice. While we could have performed a prospective study with periodic patient tracking  this design would have altered usual care seeking behaviors.Factors associated with the early loss to follow-up of PLWHA on ART in Togo were age, sex, clinical WHO stage III or IV, presence of opportunistic infection, and type of HIV care center; moreover, many patients lost to follow-up died. These results suggest specific groups that could be targeted with active case follow-up or SMS messaging.