The optimal therapeutic strategies for patients presenting with advanced disease at HIV-1 diagnosis are as yet incompletely defined.All patients presenting at two outpatient clinics in 2000-2009 with an AIDS-defining clinical condition or a CD4+ T cell count < 200/μL at HIV-1 diagnosis were analyzed for the presence of combined immunovirological response, defined by the concomitant presence of an absolute number of CD4+ T cells > 200 cells/μL and a plasma HIV-1 RNA copy number < 50/mL after 12 months of HAART.Among 102 evaluable patients, first-line regimens were protease inhibitors [PI]-based in 78 cases (77%) and efavirenz-based in 24 cases (23%). The overall response rate was 65% (95% CI: 55-74), with no differences by gender, age, nationality, route of transmission, hepatitis virus coinfections, presence of AIDS-defining clinical events, baseline HIV-1 viral load, or type of regimen . Response rate was significantly better with higher baseline CD4+ T cell counts . Median time on first-line antiretroviral therapy was 24 months (interquartile range: 12-48). Switch to a second line treatment occurred in 57% of patients, mainly for simplification (57%), and was significantly more common with PI-based regimens [adjusted hazard ratios (AHR) with respect to efavirenz-based regimens: 3.88 for unboosted PIs  and 4.21 for ritonavir-boosted PI ] and in older subjects (≥ 50 years) . Overall mortality was low (3% after a median follow up of 48 months).Our data indicate that a favorable immunovirological response is possible in the majority of naive patients presenting at HIV-1 diagnosis with AIDS or low CD4+ T cell counts, and confirm that starting HAART with a more compromised immune system may be associated with a delayed and sometimes partial immune recovery. Simpler regimens may be preferable in this particular population. In Human Immunodeficiency Virus type 1 (HIV-1) infection, the introduction of highly active antiretroviral therapy (HAART) has determined a marked decrease in HIV-1 related morbidity and mortality  or with Despite the general consistency of all HIV-1 treatment guidelines in recommending antiretroviral therapy in the presence of clinical and/or laboratory situations indicating immune deterioration ,17, therThe aim of this retrospective study was to identify, in a cohort of HIV-1 infected patients presenting at the diagnosis with an advanced disease, rate and potential determinants of an adequate and sustained immunovirological response, defined by achieving an absolute number of CD4+ T lymphocytes > 200 cells/μL together with plasma HIV-1 RNA levels below the threshold of detection (50 copies/mL) after 12 months of HAART. We considered particularly relevant to evaluate the efficacy of NNRTI-based regimens compared to PI-based regimens with or without ritonavir boost. A secondary objective of our analysis was to evaluate predictors of switching to a second line antiretroviral therapy.We retrospectively selected, among all the patients tested positive for antibodies to HIV-1 between 2000 and 2009 at the outpatient clinics of the Dpt. of Clinical Medicine and the Dpt. of Infectious and Tropical Diseases, "Sapienza" University of Rome, the clinical records of those who presented with a clinical AIDS-defining condition and/or with a CD4+ T cell count below 200/μL. Stage of HIV-1 disease was graded according to the CDC case definition [All patients included in the study gave their informed consent to data collection and the retrospective study was approved by the review board at our Institution.2 test, calculating odds ratios with 95%CI by Mantel-Haenszel estimates, or the Fisher test in the presence of at least one cell with < 5 expected cases in contingency tables. Kaplan-Meier survival analysis with log-rank test and Cox regression were used to analyse time on treatment and to calculate probabilities and hazard ratios for changing first-line treatment. In order to adjust for potential confounders, analyses included multivariable logistic regression analyses with estimates of adjusted odds ratios and 95%CI for immunovirological success, and Cox regression models with estimates of adjusted hazard ratios for switch from first-line treatment. The assumption of proportional hazards was tested by the ln(-ln) transformation procedure. Significance levels were set at 0.05. All the analyses were performed with the SPSS software, Version 17.0 .Quantitative variables were summarized with medians and interquartile ranges. Categorical variables were summarized using proportions. The main outcome measure was represented by immunovirological success, defined by a CD4+ T cell count above 200/μL plus undetectable (< 50 copies/mL) HIV-1 RNA plasma levels at month 12  from the start of treatment. Categorical data were compared using the χPneumocystis jirovecii pneumonia, 7 (16%) for esophageal candidiasis, 6 (14%) for neurotoxoplasmosis, 4 (9%) for tuberculosis, 4 (9%) for a wasting syndrome, 3 (7%) for disseminated cryptococcosis, 2 (5%) for Kaposi's sarcoma, and 1 (2%) for cytomegalovirus retinitis. At the time of diagnosis 36 patients (35%) were in CDC stage A3, 23 (23%) in B3, 1 (1%) in C2 and 42 (41%) in C3. Coinfection with hepatitis viruses was present in 9 patients (9%). The median values of CD4+ T cells and plasma HIV-1 RNA at diagnosis were 104.5/μL (IQR: 48-160), and 5.26 log10/mL (IQR: 4.99-5.58).Based on clinical records, 107 subjects were identified. Of these, 5 were excluded from the analysis because of short follow up , or unconfirmed eligibility criteria , for a total of 102 evaluable patients. The proportion of late presenters  across the entire study period (2000-2009) was 28.7%. The main patients' characteristics at start of treatment, as well as the proportion of patients with immunovirological success and with switch of treatment are shown in Table First-line regimens were PI-based in 78 cases (77%) and NNRTI-based in the remaining 24 cases (23%), and included in all cases two NRTIs as backbone. Among subjects on PI-based regimens, 16 were taking an unboosted PI: , and 62 a ritonavir-boosted PI . The only NNRTI used was efavirenz (24 patients). The main characteristics of patients according to treatment (PIs or efavirenz) are shown in Table 10 vs. > 5 log10 copies/mL)  was achieved in 66 out of 102 patients, for an overall response rate of 65% (95% CI: 55-74). No difference in response rate was observed by gender, age (< 50 vs. ≥ 50 years), nationality , route of transmission, hepatitis virus coinfections, presence of AIDS-defining events at diagnosis, or baseline HIV-1 viral load (< 5 log10/copies/mL in the PIs group compared to 3.35 log10 in the efavirenz group (p = 0.94).Response rate was however significantly different by baseline CD4+ T cell levels. The proportion of patients who had both undetectable (< 50 copies/mL) viral load and CD4+ T cell counts above 200/μL at 12 months was significantly higher among patients with a baseline CD4+ T cell count > 100/μL  compared to patients with CD4+ counts below this threshold . No significant differences were also observed between patients on PIs and on efavirenz: after 12 months, 63% of patients treated with a PI-based HAART (49/78) and 71% of patients treated with efavirenz (17/24) achieved the immunovirological primary response measure (p = 0.47) .Finally, among patients taking PIs there was no significant difference between subjects treated with and without a ritonavir booster. The average increase from baseline in CD4+ T cells was 171/μL in the boosted PIs group vs. 194/μL in the unboosted PIs group (p = 0.52), with a viral load reduction of 3.41 and 3.08 log10 vs. < 5 log10 copies/mL) as covariates was constructed. The results of this analysis substantially confirmed the predictive role of a baseline CD4+ T cell value ≥ 100/μL on immunovirological success, with an adjusted odds ratio of 2.93 compared to CD4+ T cells < 100/μL , with no significant associations for the other variables  or the presence of an AIDS-defining condition at baseline , the AHRs for switch, compared to NNRTI-based regimens, were 4,21  for ritonavir-boosted PIs regimens and 3.88  for unboosted PIs regimens , and switch to a second line treatment occurred in 58 out of 102 patients (57%), mainly for therapy simplification 33/58, 57%). Reasons for change are reported in Figure 2-48, and3/58, 57%Overall mortality was low, and no patient died during the first year of observation; subsequently one patient with non-Hodgkin lymphoma and other two with severe opportunistic infections died between 20 and 48 months, for an overall mortality of 3% during an average follow up of 45 months.Although guidelines for the diagnosis and treatment of HIV-1 infection recommend starting therapy when number of CD4+ T cells is < 500-350/μL ,17, it iConsidering the combined immunovirological outcome, observed response rate in our series was 65%, with a low mortality (3%) during follow up. Although the proportion of responder subjects may appear slightly lower compared to other studies performed in naive patients ,27, it iAs previously reported, an important goal of the present analysis was to identify predictors of immunovirological success. This outcome was not associated with age, nationality, route of transmission, clinical stage of HIV-1 disease, and HIV-1 viral load at baseline. Conversely, CD4+ T cell count at entry represented a significant predictor: patients starting HAART with CD4+ T cells > 100/μL had a 3 times higher probability to reach an immunovirological response at 12 months. This is consistent with other data showing that starting HAART in a poor immune condition is associated with a delayed, and sometimes partial, immune recovery and suggests that a discordant response to HAART  may be more frequent in patients starting therapy with a more severe degree of immune deterioration .Regarding type of first-line treatment, in terms of treatment response our data showed that PI-based regimens were not superior to those based on efavirenz. These data are consistent with the recent ACTG 5142 study, that showed among treatment-naive patients no significant difference in immune recovery after 48 weeks between lopinavir/ritonavir and efavirenz as initial therapy , and witAn important point emerged from our study is represented by the differences in immune recovery after one year of therapy in subjects with different routes of transmission. In particular, the 12 month CD4+ T cell recovery seems to be significantly higher in MSM than in heterosexuals. We evaluated potential confounding factors, such as age or AIDS diagnosis, without detecting significant differences. It could be hypothesized that the two groups differ in terms of adherence to the therapeutic prescriptions. It could be particularly relevant to explore this issue promoting studies on adherence to antiretroviral therapy in late presenters, in order to evaluate this hypothesis and simplify as much as possible the treatment in patients identified as less compliant with drug prescriptions. Selecting a regimen that ensures maximum adherence to get as soon as possible an adequate immune recovery is particularly important in these advanced patients, who may have more compromised clinical and/or immunological conditions.Our study has some limitations: a limited sample size, that may have reduced the power to detect differences between groups, a non-randomized assignation of treatment, and the lack of adherence measurements. The findings related to treatment should therefore be taken cautiously. Moreover, we cannot extend the validity of these observations to other NNRTIs, such as nevirapine and etravirine. Nonetheless, our data suggest that based on a background of similar immunovirological response, efavirenz-based regimens could have an advantage over PI-based regimens because of their simpler administration characteristics, that might promote better adherence in a sustainable long-term approach. Finally, in terms of possible therapeutic choices, it is important to consider in these particular patients the potential use of other recently available treatment options ,29 repreDespite increasing progress in treatment of individuals with HIV-1 disease, a late diagnosis remains the main factor contributing to the occurrence of new AIDS cases and persistence of a high mortality, and represents a major obstacle to an effective prevention of infection spread in Western countries. The implementation of information campaigns remains essential to promote the adoption of effective preventive behaviours and to achieve an earlier and more diffuse HIV-1 testing. Our data indicate the possibility to reach a favorable immunovirological response in the majority of naive patients presenting at HIV-1 diagnosis with AIDS or low CD4+ T cells, and confirm that starting HAART with a more severely compromised immune system may be associated with a delayed, and sometimes partial, immune recovery. Furthermore, these observations strongly suggest that simpler regimens may be a preferable therapeutic option in this particular population due to their better sustainability in a long-term prospective.The authors declare that they have no competing interests.All authors 1) have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; 2) have been involved in drafting the manuscript or revising it critically for important intellectual content; and 3) have given final approval of the version to be submitted.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/11/341/prepub


There is lack of a practical biomarker to predict sustained virological response (SVR) in chronic hepatitis B (CHB) patients undergoing peginterferon alfa-2a (PEG-IFN). The aim of this pilot study was to identify immunological features associated with SVR.Consecutive 74 CHB patients receiving 24 weeks (for hepatitis B e antigen (HBeAg)-positive) or 48 weeks (for HBeAg-negative) PEG-IFN, were prospectively enrolled. Serum HBV viral loads, hepatitis B surface antigen (HBsAg), CXCL9, IFN-γ-inducible protein 10 (IP-10), interferon-gamma (IFN-γ) and transforming growth factor beta (TGF-β) were measured at baseline and week 12. SVR was defined as HBeAg seroconversion combined with viral load <2000 IU/mL in HBeAg-positive (n=36), and viral load <2000 IU/mL in HBeAg-negative patients (n=38) at 48 weeks after the end of treatment.7 IU/mL and on-treatment HBV viral load, HBsAg decline >10% at week 12 were predictors of SVR. The performance of CXCL9 in predicting SVR was good in patients with HBV DNA <2.5 x 107 IU/mL, particularly in HBeAg-negative CHB cases .Nineteen patients (25.7%), 7 in HBeAg-positive and 12 in HBeAg-negative, achieved SVR. There were significant declines of HBV DNA, HBsAg, IP-10 and IFN-γ levels at week 12. In multivariate analysis, pre-treatment CXCL9 >80 pg/mL, HBV DNA <2.5 x 10Pre-treatment CXCL9 level has the potential to select CHB patients who can respond to PEG-IFN, especially in HBeAg-negative patients with low viral loads. Chronic hepatitis B virus (HBV) infection remains a challenging global health problem, with more than 350 million carriers worldwide . The spePeginterferon-alpha-2a (PEG-IFN), which has direct antiviral and immuno-modulatory effects, is currently one of the first-line treatment options for CHB ,7. AntivBased on the immuno-modulatory properties of PEG-IFN, host immune status may have influence on the efficacy of PEG-IFN for CHB. In recent years, several studies have shown the potential roles of cytokines and chemokines in chronic viral hepatitis. CXCL9 (monokine induced by IFN-γ [MIG]) and IP-10  have been reported to play important roles during hepatitis flares in CHB . In patiCurrently, pre-treatment and on-treatment predictors of SVR in CHB patients under PEG-IFN therapy remain unsatisfactory to meet clinical need. The aim of this pilot study was to investigate the dynamics of cytokines and chemokines during PEG-IFN treatment, and to evaluate the baseline and on-treatment immunological and viral factors associated with SVR in CHB patients treated with PEG-IFN.From January 2010 to July 2011, consecutive 74 CHB patients receiving PEG-IFN alfa-2a 180µg per week at the Taipei Veterans General Hospital were prospectively enrolled. All patients were positive for serum HBsAg for more than 6 months and patients receiving PEG-IFN therapy fulfilled the treatment criteria for CHB according to the American Association for the Study of Liver Disease (AASLD) treatment guidelines, i.e. serum ALT levels >80 U/L [2 x upper limit of normal (ULN)] with HBV DNA >20,000 IU/mL in HBeAg-positive patients or >2,000 IU/mL in HBeAg-negative patients  and CTGGTTCACGCCTTC [FAM], respectively) [Four SNPs of IL28B including rs8105790, rs12979860, rs8099917 and rs10853728 were chosen according to previous reports and our study ,25–28,31ctively) . The genctively) .All statistical analyses were performed using the Statistical Package for Social Sciences . Values were expressed as median (ranges) or as mean ± standard deviation when appropriate. The correlation between serum ALT and chemokine levels were tested by Spearman’s test. Pearson chi-square analysis or Fisher exact test was used to compare categorical variables, while the Student t test or Mann-Whitney U test was used to compare continuous variables. Wilcoxon signed ranks test was used to compare serial changes in virological and immunological factors. Variables with p<0.1 were analyzed by multivariate logistic regression analysis to identify independent variables for predicting SVR. The best cut-off value of each variable was determined by the receiver-operating characteristic (ROC) curve (Youden index) using MedCalc . A 2-tailed p value <0.05 was considered statistically significant.Baseline characteristics of the 74 CHB patients were summarized in Overall, 19 patients (25.7%) had achieved SVR at 48 weeks after the end of PEG-IFN treatment. Among the 36 HBeAg-positive patients, 12 (33.3%) achieved HBeAg seroconversion, including 10 of the 30 patients (33.3%) receiving 24-week course of treatment and 2 of the 6 patients (33.3%) receiving 48-week course of treatment; whereas only 7 (19.4%) finally achieved SVR, including 6 of the 30 patients (20%) receiving 24-week course of treatment and 1 of the 6 patients (16.7%) receiving 48-week course of treatment. In HBeAg-negative patients, 12 (31.6%) achieved SVR and 2 cases (5.3%) achieved HBsAg clearance at 48 weeks after the end of PEG-IFN treatment. During the extended follow-up period between 24 to 48 weeks post treatment, one HBeAg-positive patient developed HBeAg seroconversion and one HBeAg-negative patient had viral relapse.Dynamic changes of serum HBV DNA, HBsAg, cytokine and chemokine levels from baseline to week 12 of PEG-IFN treatment were shown in In patients with SVR, CXCL9 levels significantly decreased from baseline to week 12, and further decreased at EOT  and HBsAg levels  at week 12 of PEG-IFN therapy. In contrast, no significant correlations were noted between IP-10 levels decline and declines of viral load or HBsAg levels.Serum ALT, CXCL9 and IP-10 levels were measured at each time point during PEG-IFN treatment for correlation analysis . As shown in 7 IU/mL and CXCL9 >80 pg/mL were pre-treatment predictors of SVR . Among the 28 patients with baseline CXCL9 >80 pg/mL, 24 (85.7%) had ever achieved HBV DNA <20,000 IU/mL, whereas in the 46 patients with baseline CXCL9 <80 pg/mL, only 26 (56.5) had ever achieved HBV DNA <20,000 IU/mL (p=0.019).In order to identify patients who had higher chance of SVR before PEG-IFN treatment, an algorithm based on combination of baseline serum CXCL9 and HBV DNA levels was established . PatientInterferon therapy for CHB remains a clinical challenge. Although successful PEG-IFN treatment may induce a durable response and reduce liver-related complications, most of patients could not achieve virological response –13, and In the current study, the HBeAg seroconversion rate and SVR rate in HBeAg-positive patients receiving 24-week PEG-IFN treatment  were comparable with the results reported in previous studies ,33,34. IDeclines of serum IP-10 levels have been observed during PEG-IFN therapy in HBeAg-positive CHB patients . In our The finding that older patients have higher rates of SVR in univariate analysis might relate to lower viral loads in elder people. Although IL28B SNPs have been shown to predict SVR in patients with chronic hepatitis C and correlate with hepatitis activity in CHB ,25–27, tBaseline CXCL9 level significantly correlates not only with SVR, but also with on-treatment viral suppression. This finding supports a stronger host immune response at baseline having a higher chance of SVR under interferon treatment. A recent finding also showed that HBeAg-negative CHB patients with greater baseline HBV-specific CTL responses had a better on-treatment control of HBV replication during PEG-IFN treatment .+ T cells, effector CD8+ T cells and innate-type lymphocytes, such as natural killer (NK) and NKT cells. In contrast, the induction of CXCL9 is restricted to IFN-γ, and its function is predominantly in recruiting CD8+ cytotoxic T lymphocytes [CXCL9 and IP-10 are chemokines that bind to the cell surface chemokine receptor CXCR3, which is highly expressed on effector T cells and plays an important role in T cell trafficking and function ,41. An aThe strong correlation of baseline CXCL9 levels with SVR indicates that CXCL9 might serve as a marker to select CHB patients suitable for PEG-IFN therapy, especially in HBeAg-negative cases with low viral loads. In contrast, the SVR rate in patients with high viral loads was low regardless of their baseline CXCL9 levels, suggesting that host antiviral immunity might be overwhelmed by high viral loads.As a pilot study, the case number was small. It was also due to fewer than 5% of CHB patients in Taiwan had the will to receive PEG-IFN as initial antiviral treatment. Therefore, it is important to identify a pre-treatment marker to predict response to PEG-IFN, not only to encourage patients to receive PEG-IFN treatment but also to save the medical resources for those with a high chance of response. Further large and long-term follow up studies are needed to determine the appropriate cutoff level of CXCL9, and to observe the predictive value of CXCL9 on delayed virological response and HBsAg clearance.In conclusion, CXCL9 might be used to select appropriate CHB patients to receive PEG-IFN treatment, especially in HBeAg-negative patients with low viral loads.Table S1Univariate and multivariate analyses of factors associated with sustained virological response in HBeAg-positive patients (n=36).(DOC)Click here for additional data file.Table S2Univariate and multivariate analyses of factors associated with sustained virological response in HBeAg-negative patients (n=38).(DOC)Click here for additional data file.


Approximately 4 million of people are co-infected with HIV and Hepatitis B virus (HBV). In resource-limited settings, the majority of HIV-infected patients initiate first-line highly active antiretroviral therapy containing lamivudine (3TC-containing-HAART) and long-term virological response of HBV to lamivudine-containing HAART in co-infected patients is not well known.10 IU/mL and 4.47 log10 copies/mL, respectively. At 12 months, 67% of patients achieved HBV DNA suppression: 100% of HBeAg-negative patients and 47% of HBeAg-positive. Seventy-three percent of patients had HIV RNA below 50 copies/mL. The cumulative rates of maintained HBV-DNA suppression among the 23 patients who achieved HBV-DNA suppression were 91%, 87%, and 80% at 1, 2, and 4 years respectively. Of 17 patients who maintained HBV-DNA suppression while still on 3TC, 4 (24%) lost HBsAg and 7 of 8 (88%) HBeAg-positive patients lost HBeAg at their last visit . HBV breakthrough was observed only in HBeAg-positive patients and 6 of 7 patients presenting HBV breakthrough had the rtM204I/V mutations associated with 3TC resistance along with rtL180M and/or rtV173L.HIV-HBV co-infected patients enrolled in the PHPT cohort  and initiating a 3TC-containing-HAART regimen were included. HBV-DNA, HIV-RNA, CD4+ T-cell counts and alanine transaminase were measured at baseline, 3 months, 12 months and then every 6 months up to 5 years. Kaplan-Meier analysis was used to estimate the cumulative rates of patients who achieved and maintained HBV-DNA suppression. Of 30 co-infected patients, 19 were positive for HBe antigen (HBeAg). At initiation of 3TC-containing-HAART, median HBV DNA and HIV RNA levels were 7.35 logAll HBeAg-negative patients and 63% of HBeAg-positive HIV-HBV co-infected patients achieved long-term HBV DNA suppression while on 3TC-containing-HAART. This study provides information useful for the management of co-infected patients in resource-limited countries where the vast majority of co-infected patients are currently receiving 3TC. In 2010, the World Health Organization (WHO) estimated that 34 million people were HIV infected worldwide Current guidelines for the use of antiretroviral agents in HIV-1-infected patients Lamivudine is a cytidine analogue that inhibits the reverse transcriptase of both HIV and HBV In Thailand, since the national scale-up of ART in 2004 Patients were enrolled in the prospective multicenter Program for HIV Prevention and Treatment (PHPT) cohort  of HIV-infected adults on antiretroviral therapy in Thailand and provided written informed consent at entry. This cohort study was approved by the Thai Ministry of Public Health and ethic committees at Chiangrai Prachanukroh, Prapokklao, Chonburi, Bhuddasothorn, Somdej Prapinklao, Nopparat Rajathanee, Bhumibol Adulyadej, Buddhachinaraj, Hat Yai, Samutsakorn, Nakhonpathom, Maharaj Nakornratchasrima, Sanpatong Hospitals. All investigators conducted the study according to the principles expressed in the Declaration of Helsinki. This sub-study was also approved by the ethic committee of the Faculty of Associated Medical Sciences, Chiang Mai University.At entry, prior to starting HAART, all patients were screened for HBsAg and anti-HCV antibodies and had CD4+ T-cell count and plasma HIV RNA load performed. Following HAART initiation, CD4+ T-cell enumeration and plasma HIV RNA were measured every 6 months. Patients received a quarterly clinical biological follow-up and compliance was assessed at each visit by pill count and self-reporting.Patients were included in this analysis if 1) HBsAg positive, 2) receiving HAART regimens which included 3TC (150 mg twice a day), 3) stored blood samples collected prior to 3TC initiation (baseline), and on HAART  were available, and 4) HBV DNA was detectable at baseline.10 IU/mL). HIV RNA was quantified using the COBAS Amplicor HIV-1 Monitor Test v.1.5.  (lower limit of detection: 1.70 log10 copies/mL) and the Abbott real-time HIV RNA™ assay, Abbott, (lower limit of detection: 1.6 log10 copies/mL).HBsAg and HBeAg were tested at baseline using DiaSorin ETI-MAK-4 and DiaSorin ETI-EBK PLUS , respectively. HBsAg was tested in patients on 3TC treatment using the MonoLisa® HBsAg ultra with a sensitivity of 50 pg/mL . HBV viral load was quantified using the Abbott real-time HBV DNA™ assay, Rungis, France (lower limit of detection 1.18 log10 IU/mL since some samples were diluted 1∶10 due to insufficient volume); virological breakthrough defined as an initial decline >2 log10 IU/mL followed by an increase of HBV DNA >1 log10 IU; and maintained viral suppression defined as HBV DNA level persistently <2.18 log10 IU/mL.HBV responses to 3TC were categorized according to the APASL recommendations http://www.mbio.ncsu.edu/bioedit) and HBV genotype was identified by phylogenetic analysis. HBV pol sequences were analyzed for polymorphisms and mutations known to be associated with 3TC resistance through comparison with wild-type reference sequences of similar genotype All baseline samples as well as any sample with detectable HBV DNA on 3TC-containing-HAART were tested for HBV resistance mutation; HBV DNA sequencing was performed as previously described Baseline characteristics are reported as percentage with 95% confidence interval (95%CI) or medians with interquartile ranges (IQR) and were compared according to HBeAg status using Fisher’s exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. Kaplan-Meier analysis was used to estimate the cumulative rates of achieving serum HBV DNA and, in those who achieved HBV DNA suppression, the duration of maintaining such suppression. Duration of HBV DNA suppression was counted from the date of first viral suppression until the date of first detectable HBV DNA or, if a patient was lost to follow-up or switched to a regimen without 3TC, the date of last undetectable HBV DNA load. Log-rank test was used to compare the cumulative rates of virological responses between HBeAg-positive and HBeAg-negative patients. For the analysis of association between the baseline CD4, HIV RNA, HBV DNA levels and virological responses to 3TC-containing HAART, continuous data were dichotomized according to the median baseline values and analysis was performed using Fisher’s exact or log-rank tests. Statistical significance was defined as p<0.05. Data were analyzed using STATA™ version 10.1 software .Of 1,448 HIV infected adults on HAART, 122 (8.4%) tested HBsAg-positive. Thirty patients met all criteria for this analysis i.e. receiving 150 mg twice a day (bid) of 3TC as part of HAART, blood samples collected at baseline and on 3TC-based treatment and detectable HBV DNA at baseline . Ninetee10 , and 47%  of patients achieved HBV DNA suppression. At 12 months, median HBV DNA reduction was 4.40 log10  IU/mL and 20 patients  of patients achieved HBV DNA suppression.After 3 month of HAART, median reduction of HBV DNA was 3.86 logThe rate of HBV DNA suppression at 12 months was significantly higher among HBeAg-negative patients than among HBeAg-positive patients , 2 had a viral breakthrough and one had no long-term sample available.10 IU/mL), one had a viral breakthrough at 24 months of treatment, and one switched treatment regimen . The baseline HBV DNA levels did not differ between the two baseline HIV RNA groups . At one year, there was no difference in HBV response (67% versus 67%) by baseline HIV RNA group. Furthermore, there was no difference in response during 5-years of 3TC-containing HAART .To analyze the relation between baseline HIV RNA load and HBV virological response to 3TC-containing HAART, patient baseline HIV RNA levels were dichotomized according to the median baseline HIV RNA level . Eighteen (78%) maintained HBV DNA suppression up to their last visit, 4 (17%) had a HBV breakthrough, and one changed drug regimen after 15 months of 3TC treatment . The cumOf the 18 patients who maintained long-term HBV DNA suppression, 17 had a sample available for HBsAg testing. Four patients (24%) lost HBsAg at their last visit; one was HBeAg positive and three were HBeAg negative when initiating of 3TC-based HAART. Among the 8 HBeAg positive patients, 7 lost HBeAg at their last visit.There was no mutation associated with resistance to 3TC observed in all 30 patients before initiation of 3TC-containing-HAART. The 5-year cumulative rate of 3TC resistance was 20% (6/30); all of which was found in HBeAg positive patients. The mutations were found in 6 of 7 patients with viral breakthrough. Early viral breakthrough (within 1 year of therapy) occurred between 4 and 12 months in 4 patients. One patients had the HBV mutation ntG741A (G to A nucleotide at position 741), resulting in the known 3TC-associated resistance mutation rtM204I. This mutation led to the concomitant substitution of tryptophan to stop codon at position 196 (sW196stop) in the surface protein. The ntT843G mutation of unknown significance was also observed and resulted in the change from asparagine to lysine in the reverse transcriptase protein (rtN238K). In the 3 other patients, the viral breakthrough was not associated with the detection of HBV resistance mutations; however the M204V mutation was detected later during the follow-up in 2 patients, (i) at 42 months, along the compensatory resistance mutations rtV173L+L180M in one patient, and (ii) at 78 months with rtL180M mutation in one patient. No long-term HBV sequence was available for the third patient due to subsequent switch to non-3TC including regimen.Late HBV breakthrough occurred in 3 patients and was associated with the emergence of 3TC-resistance mutations: rtV173L+L180M+M204I, rtL180M+M204V and rtL180M+M204I. Four patients never achieved undetectable HBV DNA but no resistance mutations were found before they switched to non-3TC regimen or recieved add-on TDF.10  and 73% patients achieved undetectable HIV RNA load (<1.7 log10 or 50 copies/mL). At 12-month, the median HIV RNA reduction was 2.92 log10  copies/mL and 73% patients achieved undetectable HIV RNA load. Reduction of HIV RNA levels and proportions of undetectable HIV RNA were similar irrespective of baseline HBV DNA level and HBeAg status (6 cells/L at baseline to 247 (IQR: 197–374) at 12-month and 472 x106 cells/L at 5 years of treatment, respectively. Median ALT was 30 (IQR: 20–39) IU/L and decreased but not significantly to 21 IU/L (IQR: 16–29) at 5 years of 3TC treatment. Kinetics of CD4+ T-cell counts and serum ALT levels in HIV-HBV co-infected patients after initiation of 3TC-containing HAART are showed in 6 cells/L) had similar rates of undetectable levels of both HBV DNA and HIV RNA over 5 years of 3TC-containing HAART as those with CD4 T-cell counts below the median . Also, over 5-years of 3TC-containing HAART, there was no difference in increase of absolute CD4+ T-cells count among HBV virological responders and non-responders.At 3-month, the median reduction of HIV RNA was 2.92 logg status . Six pat10 IU/mL. A recent study conducted in Kenya 10 IU/mL and similar to the level in our study. Furthermore, we found no relation between the baseline HIV RNA level and HBV response to 3TC-containing HAART or between the baseline HBV DNA level and HIV response to 3TC-containing HAART. Baseline CD4 count was not associated with either HBV or HIV virological response. In addition, over 5-years of 3TC-containing HAART, increases of absolute CD4+ T-cells count were not different among HBV virological responders and non-responders.We analyzed the long-term HBV and HIV virological response in a group of 30 HIV-HBV co-infected patients, 63% HBeAg-positive, who received 3TC, as part of HAART regimen. After 12 months of 3TC-containing-HAART, the rate of HBV DNA suppression in our study was 67%, compared to the 40% reported in the international collaborative (CAESAR) study conducted in Canada, Australia, Europe and Africa 10 IU/mL while it was 2.18 log10 IU/mL in our study. The higher response rate in our study may be due to a better compliance of patients to their treatment as evidenced by 73% of patients achieving HIV RNA below 50 copies/mL at 12 months and most of patients had undetectable HIV RNA, except some with high replication of drug-resistant strains. Another possibility could be that the HBV genotypes B and C are more sensitive to 3TC than genotypes A and D, which require confirmation with in vitro experiments. HBV DNA suppression was maintained in all HBeAg-negative patients. The higher rate of response to 3TC treatment and duration of HBV DNA suppression among HBeAg-negative patients suggest that, in resource-limited countries, HBeAg testing may be a valuable marker to predict the virological response to 3TC and could be considered when initiating in HIV-HBV co-infected patients the first-line HAART which usually includes 3TC. Other studies conducted among patients with chronic HBV infection in Japan and Brazil showed that HBeAg-negative patients had better HBV response to 3TC Among the 23 patients who had achieved HBV DNA suppression, 18 (78%) maintained HBV DNA suppression over a median of 51 months. This rate is much higher than the 9% reported by Benhamou et al, in HIV-HBV co-infected patients after 4 years of treatment with the same dosing of 3TC HBeAg seroconversion and HBsAg loss are usually associated with favorable clinical outcome. Twenty-four percent (4/17) of patients lost HBsAg and 88% (7/8) of HBeAg-positive patients lost HBeAg at their last visit (median duration of 59 months). Although our study had a limited number of patients, our results are consistent with those reported in a recent study conducted in Taiwan among HBV-HIV infected patients receiving 3TC-containing HAART (median duration of 34 months), 6% (6/108) of HBsAg loss and 46% (21/46) of HBeAg seroconversion pol gene. This may be due to the emergence of mutations outside the rt domain or other mechanisms yet to identified.One major limitation of treating HBV with 3TC monotherapy is the rapid emergence of resistance mutations. In HBV-HIV-1 co-infected patients, resistance mutations to 3TC have been shown to occur at a rate of 15–20% per year A nucleotide analogue, TDF, has been shown to be active against both wild-type and 3TC resistant HBV In conclusion, our study shows that all HBeAg negative patients and a significant number of HBeAg positive HIV-HBV co-infected patients can achieve long-term HBV DNA and HIV suppression on 3TC containing HAART. The results of this study provide further information which may be useful for the management of HIV-HBV co-infected patients in resource-limited countries where the vast majority of HIV-HBV co-infected patients are currently receiving 3TC.Table S1Summary of HBV DNA and HIV RNA loads of HIV-HBV co-infected patients on lamivudine-containing HAART.(DOCX)Click here for additional data file.


Real world data on the development of drug resistance after virologic failure (VF) on a protease inhibitor (PI)-based antiretroviral (ARV) regimen are limited. The I50L substitution in protease is the primary mutation associated with atazanavir drug resistance. The primary objective was to compare the prevalence of I50L from VF patients on an unboosted atazanavir (ATV)-based regimen vs. those on a ritonavir-boosted ATV (ATV/r)-based regimen regardless of prior treatment history.IMPACT is a large cross-sectional study of patients with VF while on an atazanavir-containing regimen that was conducted at 220 sites in 8 countries. Demographic/medical information and blood for a genotype resistance test were collected at a single study visit. A substudy evaluated the efficacy of the regimen subsequent to the atazanavir-containing regimen based on when atazanavir was used in therapy.IMPACT enrolled 703 patients, and genotype resistance tests were able to be performed for 678. 67 had been on both ATV and ATV/r, and 55 had incomplete ARV histories. Overall, 48/556 evaluable patients had virus with an I50L: 12/96 (12.5%) on ATV and 36/460 (7.83%) on ATV/r (p=0.116). Most patients had been on another PI prior to atazanavir.88/678 patients were on atazanavir (either ATV or ATV/r) as a first PI, and 69 had a complete ARV history. 3/19 (15.8%) who started ATV and 5/50 (10%) who started ATV/r had an I50L at VF. Phenotype resistance tests were performed for these patients: 55 tests showed full susceptibility while 12 tests showed reduced susceptibility to atazanavir. The viral isolates from these 12 patients remained fully sensitive to both lopinavir and darunavir.Enrollment for the substudy was below the target enrollment, and sample sizes in all of the comparison groups were too small for meaningful statistical inference.In a large clinical cohort of subjects failing atazanavir-based therapy with resistance data, I50L is uncommon in subjects with VF on atazanavir. Most PI-naive subjects failing an atazanavir-based regimen failed with virus susceptible to atazanavir, and all viral isolates were sensitive to the other PIs commonly used to treat virus with PI drug resistance. These real world data provide further support of clinical trial data that have shown preservation of treatment options after VF when atazanavir is used as a first PI.


Current guidelines for providing antiretroviral therapy (ART) in South Africa's public sector programme call for switching patients from first-line to second-line treatment upon virologic failure as indicated by two consecutive viral loads above 5000 copies/ml, but without laboratory evidence of viral resistance. We modelled the net cost of adding resistance testing for patients with virological failure and retaining patients without resistance on first-line therapy, rather than switching all failures to second-line therapy.Costs were estimated for three scenarios: routine maintenance ; resistance testing ; and limited testing . A Markov model was used to estimate the cost of each arm over five years after first line initiation. Rates of treatment failure, viral resistance and treatment costs were estimated with primary data from a large HIV treatment cohort at a public facility in Johannesburg. Future costs were discounted at 3%.Virological failure rates over five years were 19.8% in routine maintenance and 20.2% in resistance testing and limited testing; 16.8% and 11.4% of failures in routine and limited testing, respectively, did not have any resistance mutations, resulting in 3.1% and 2.0% fewer patients switching to second-line ART by the end of five years. Treatment costs were estimated at US$526 and $1268 per patient per year on first-line and second-line therapy, respectively; a resistance test cost $242. The total average cost per patient over five years was $2780 in routine maintenance; $2775 in resistance testing; and $2763 in limited testing.Incorporating resistance testing into treatment guidelines in South Africa is potentially cost-neutral and can identify other reasons for failure, conserve treatment options, and generate information about emerging resistance patterns. Research in South Africa suggests that a sizable minority of HIV/AIDS patients on antiretroviral therapy (ART) with detectable viral loads remain susceptible to first-line antiretroviral drugs, and are thus apparently failing treatment without evidence of drug resistance. In three cohort studies of adult patients receiving standard ART in KwaZulu-Natal and Gauteng provinces -3, 16.5%South Africa's guidelines for adult ART call for patients to be switched from first-line to second-line therapy following virological failure . ResistaWe hypothesized that despite the relatively high cost of performing resistance assays, resistance testing for patients with detectable viral loads could prove to be cost-neutral or even cost-saving for the South African treatment programme if patients who do not have resistance are maintained on first-line drugs, rather than being switched to the more expensive second-line regimen. The objective of this analysis was to model the net cost of such a strategy, using data from a large public sector treatment facility in Johannesburg.We developed a state-transition decision (Markov) model to estimate the costs of three strategies for switching patients from first- to second-line ART over the first five years after ART initiation under the national treatment guidelines in effect from 2004 to 2010 [A hypothetical cohort of patients move through the model in six-month cycles, beginning with first-line ART initiation and continuing for a total of five years of follow up. A cycle length of six months was selected because routine viral load testing was performed every six months under the prevailing treatment guidelines. At the end of each cycle, a viral load test is done for all patients and a second confirmatory test for those whose first result is detectable (>1000 copies/ml). In the routine monitoring (RM) strategy, which reflects standard practice at the study site, all confirmed virologic failures are automatically switched to second-line therapy. In the resistance testing (RT) strategy, resistance testing is conducted at the end of the cycle for virological failures, and only patients with resistance to first-line drugs are switched to second-line therapy.Finally, we hypothesized that the probability of failing virologically but not having resistance is greater during a patient's earlier years on ART and declines in later years. We therefore estimated the costs of a limited testing (LT) strategy, in which those with confirmed virological failure any time in their first three years on ART have a resistance test at the end of the cycle in which their second consecutive detectable viral load occurs and are managed as in the RT strategy, while those on ART longer than three years at the time of confirmed failure are managed as in the RM strategy.In all scenarios, patients switched to second line remain on second line for the rest of the study period; patients still on first line at the end of each cycle continue to face cycle-specific probabilities of virologic failure in each remaining cycle. All patients remain alive and on either first- or second-line treatment at the end of the five-year modelling period.Modelling parameters for the study were estimated from the Themba Lethu Clinical Cohort, a population of approximately 10,000 adult ART patients at a previously described  public sRates of virological failure and non-resistance were estimated from the study site. Using the site's electronic medical record database (Therapy Edge™), the probability of virological failure per six-month interval on treatment was calculated for the first six intervals (three years) after first-line ART initiation, conditional on remaining alive and on ART at the site. The rate of virological failure in the last interval (months 25-36 on ART) was also applied to each six-month interval in years four and five of the model, as there were too few patients with this duration of follow up in the dataset to allow these values to be estimated from the treatment cohort. At this site, a threshold of 1000 copies/ml was used to define failure, and confirmatory viral load tests were done at intervals ranging from two weeks to several months after the first detectable result.In a previously published study presenting pooled data from our study site and another large public sector treatment facility in Johannesburg, 16.8% of patients with two consecutive detectable viral loads were found to have no known mutations . Time onEstimates of the annual unit costs of first- and second-line therapy were drawn from a published study conducted at the same site . These eth and 97.5th percentile of the simulated distributions to create 95% simulation (uncertainty) intervals (SIs) for our point estimates.To examine the sensitivity of our results to uncertainty in the model transition probabilities , we conducted a probabilistic sensitivity analysis (Monte Carlo simulation) using beta distributions for the cycle-specific virological failure rates and the cumulative non-resistance rate. Beta distributions were created with the alpha parameter equal to the total sample size minus the number of events observed and the beta parameter equal to the number of events. We then used the 2.5In addition, we conducted a series of one-way sensitivity analyses for the three main cost inputs to the model: the cost of a year of first-line treatment; the cost of a year of second-line treatment; and the cost of a resistance assay. For the treatment costs, we considered the impact of increasing or decreasing the cost per year by 20%. For the cost of a resistance test, which may vary more widely from setting to setting, we considered a cost increase or decrease of 50%.Access to anonymized patient-level data was approved by the Institutional Review Boards of Boston University and the University of the Witwatersrand.Data for 8500 patients from the Themba Lethu Clinical Cohort were included in the analysis of virological failure rates. Overall, 8.4% of patients in the sample had two consecutive detectable viral loads. The proportions of first-line patients with virological failure per six-month interval on ART are shown in Table et al [Resistance test results, as defined by Wallis et al , and timTable Table In the RT scenario, 16.8% of the failures do not have any mutations and are kept on first-line treatment, resulting in a somewhat smaller proportion (16.7%) of the original cohort ending up on second-line therapy by the end of five years. In the LT strategy, in which resistance testing is done only if the patient with virological failure started ART three years or less before, 17.8% of patients are switched to second line.Cost estimates from the baseline analysis and sensitivity analyses are shown in Figure Using the baseline cost values, the total costs of all three scenarios are almost the same. The sensitivity analysis illustrated in Figure Using recent parameter estimates from a large South African public sector treatment site, a strategy that incorporates resistance testing into decisions on whether to switch patients with first-line virologic failure to second-line therapy is potentially cost neutral. It helps identify patients failing for reasons other than viral resistance; it conserves future treatment options for these patients and spares them the additional toxicity burden of second-line drugs; and it generates better information about emerging drug-resistance patterns.The analysis presented here has a number of limitations. It is based on patient-level data from a single treatment site, which may not be representative of all sites in South Africa, and estimates parameters under treatment guidelines that have since been revised. Rates of non-resistance among virological failures by duration on ART are based on very small patient numbers and drawn from a single-site sample that may or may not be representative of all patients failing virologically. Due to data limitations, we were not able to take into account variation in the timing of viral load tests relative to the emergence of resistance or the possibility that the percentage of virologic failures that occur without resistance may vary by sub-population.Mortality and loss to follow up are also not taken into account. Treatment cost estimates reflect drug choices and prices in effect at the time of the analysis; drug prices vary widely and change frequently; and a substantial alteration in the relative costs of first- and second-line therapy could have a large impact on model results. The cost of performing a resistance test may also change with technological advances and laboratory scale.Despite its limitations, this analysis suggests that the net cost of incorporating resistance testing into treatment guidelines would not be prohibitive, and it provides a model for examining this cost under different input assumptions and treatment strategies. In countries that use viral loads to guide treatment decisions and have the capacity to conduct resistance testing at a cost similar to that cited here, incorporating it into treatment guidelines should be considered, and a follow-on analysis assessing the net benefits of this strategy, as well as its net costs, should be undertaken.The authors declare that they have no competing interests.SR, MF, IS and WS conceived of the analysis. SR designed the model, performed the analysis, and drafted the manuscript. LL and MF estimated the parameters. IS provided the data. All authors read, commented on and approved the final manuscript.


The majority of HIV-infected individuals requiring antiretroviral therapy (ART) in Russia are Injection Drug Users (IDU). Substitution therapy used as part of a comprehensive harm reduction program is unavailable in Russia. Past data shows that only 16% of IDU receiving substance abuse treatment completed the course without relapse, and only 40% of IDU on ART remained on treatment at 6 months. Our goal was to determine if it was feasible to improve these historic outcomes by adding intensive case management (ICM) to the substance abuse and ART treatment programs for IDU.IDU starting ART and able to involve a “supporter” who would assist in their treatment plan were enrolled. ICM included opiate detoxification, bi-monthly contact and counseling with the case, weekly group sessions, monthly contact with the “supporter” and home visits as needed. Full follow- up (FFU) was 8 months. Stata v10  was used for all analysis. Descriptive statistics were calculated for all baseline demographic variables, baseline and follow-up CD4 count, and viral load. Median baseline and follow-up CD4 counts and RNA levels were compared using the Kruskal-Wallis test. The proportion of participants with RNA < 1000 copies mL at baseline and follow-up was compared using Fisher’s Exact test. McNemar’s test for paired proportions was used to compare the change in proportion of participants with RNA < 1000 copies mL from baseline to follow-up.Between November 2007 and December 2008, 60 IDU were enrolled. 34 (56.7%) were male. 54/60 (90.0%) remained in FFU. Overall, 31/60 (52%) were active IDU at enrollment and 27 (45%) were active at their last follow-up visit. 40/60 (66.7%) attended all of their ART clinic visits, 13/60 (21.7%) missed one or more visit but remained on ART, and 7/60 (11.7%) stopped ART before the end of FFU. Overall, 39/53 (74%) had a final 6–8 month HIV RNA viral load (VL) < 1000 copies/mL.Despite no substitution therapy to assist IDU in substance abuse and ART treatment programs, ICM was feasible, and the retention and adherence of IDU on ART in St. Petersburg could be greatly enhanced by adding ICM to the existing treatment programs. Political, economic, and social changes accompanying the fall of the Soviet Union in the 1990’s contributed to the establishment of opium-based drug trafficking routes from Afghanistan through Russia and a rapid increase in injection drug abuse rates  and it iFew IDU in Russia are currently receiving anti-retroviral treatment (ART). Almost 90% of all people with HIV in Russia are IDU but only 6% on ART are IDU . One of Adherence to ART is critical to the effective treatment of HIV/AIDS. Adherence to prescribed doses may need to be as high as 90%-95% to achieve suppression of viral replication and prevent the development of resistant viral variants . Active Case management is an effective strategy for HIV infected IDU patients to improve substance abuse and HIV treatment outcomes ,21. HIV-A prospective cohort study of HIV uninfected IDUs at risk for HIV-infection in St. Petersburg (DAIDS HPTN 033) demonstrated the effectiveness of a case management model in retention of IDU to long-term follow-up ,7. This HIV-infected, active IDU (within the last 6 months), who were eligible to start ART or recently began ART (within the last 3 month); were able to identify a parent, relative, partner or friend (supporter) who could actively assist them in their treatment plans; and for the active users, were willing to enroll in a 10 day in-patient detoxification program, were recruited at the City AIDS Center, St. Petersburg, Russia and invited to participate in the feasibility study.Once an IDU was confirmed eligible, an enrollment visit was conducted which included an informed consent procedure, a risk assessment questionnaire including drug use and psychological status assessment, an HIV risk behavior evaluation, a physical examination of the skin looking for fresh needle marks, a urine drug screen and an alcohol breathalyzer. Enrollment also included a baseline CD4 count and HIV RNA viral load result extracted from the patients HIV care chart. If the participant was not currently on ART, ART began within 30 days of the enrollment visit. In addition, the IDU provided detailed locator information for themselves and their identified supporter.Each participant was assigned to a personal case management team: a social worker and psychologist who both were responsible for the patient’s follow-up and the development and implementation of their individual case management plan. Phone contacts or home visits were conducted by case managers when any ART clinic appointment was scheduled or missed. Any scheduled appointment was considered a missed visit after one week without re-scheduling through communication between the case manager or City AIDS Center staff and the patient. The case managers also communicated monthly with the patient supporter or more frequently during any crisis period or to assist with a scheduled or missed appointment.Follow-up study visits occurred every 2 weeks for the 8 months of study duration. The full follow-up period was determined per protocol and was set at 8 months due to budget restrictions. Each follow-up visit included an interview on recent behavior including drug use, self reported adherence to their ART regimen, social harms, a physical exam looking for fresh needle marks, and a urine drug test. Also during each follow-up visit participants received individual drug and ART counseling. ART clinic appointment schedules (and ART distribution) were variable, depended on the clinician, and ranged from every one month to every three months. During visits at 4 and 8 months the HIV risk behavior and psychological behavior questionnaire was repeated.Retention was stratified into three categories based on how many months of ART each participant received: 1. attended all clinic appointments including the 8 month follow-up visit; 2. attended some but not all clinic appointments, including the 8 month follow-up visit; 3. stopped ART before the 8 month follow-up period was complete. Adherence was determined by the final HIV RNA result that occurred between their 6–8 month follow-up visit.HIV viral load was quantified using Roche RNA PCR 1.5 with a lower limit of detection of 50 copies/mL. CD4 was quantified using FACS count, both conducted as the standard of care at the City AIDS Center.Drug abuse relapse was considered three consecutive days of drug use after a negative urine drug screen and was determined by self-report, history provided by the supporter, clinical examination for the presence/absence of fresh puncture marks and additional urine drug tests. Case management was continued regardless of drug use status.Descriptive statistics were calculated for all baseline demographic variables, baseline and follow-up CD4 count, and viral load. Median baseline and follow-up CD4 counts and RNA levels were compared using the Kruskal-Wallis test. The proportion of participants with RNA < 1000 copies mL at baseline and follow-up was compared using Fisher’s Exact test. McNemar’s test for paired proportions was used to compare the change in proportion of participants with RNA < 1000 from baseline to follow-up. Stata v10  was used for all analysis.This pilot program was conducted in compliance with the protocol, International Conference on Harmonization Good Clinical Practice E6 (ICH-GCP) and the applicable regulatory requirements and the ethical considerations stated in the declaration of Helsinki. This program was approved by institutional review boards at the University of North Carolina and the Biomedical Center in St. Petersburg.Between November 2007 and May 2008, 901 HIV positive patients at the City AIDS center in St. Petersburg, Russia were screened for inclusion in the pilot study. Among them 346 (38.4%) were injection drug users with a history of active injection in the past 6 months, and 60 (17.3%) were eligible and consented to participate. The primary reasons for ineligibility were 171 (49.4%) were not eligible for ART, 49 (14.2%) refused to attend detoxification and only 16 (4.6%) had no supporter. Among the 60 enrolled, 34 (56.7%) were male; the median age was 31 years (range 18–41); 46 (76.7%) had at least a secondary education and only 7 (11.7%) were fully employed. The median age at first drug injection was 17 years with a median of 10 years of abuse. The “supporters” were mostly female ; a parent ; or a sexual partner .At enrollment 31/60 (51.7%) were actively injecting. 29/60 (48.3%) had actively injected in the previous 6 month but were drug free at the enrollment date. Among the 31 actively injecting participants 30 (96.8%) were injecting heroin, 1 (3.2%) was injecting psycho stimulants, and 21/31 (67.7%) admitted to sharing injection paraphernalia in the past month. All 31 active users began a 10-day detoxification program but only 5 (16.1%) completed the program. However, 26/31 (83.9%) repeated the detox program at least one additional time during their 8-month follow-up period.All 60 subjects started on ART between 3 months prior to enrollment and 1 months following enrollment. Sixteen (26.7%) started ART prior to enrollment. The reasons for ART initiation were 45 (75.0%) CD4 <300 cells/mL; 31 (51.7%) RNA >50,000 copies mL; and 3 (5.0%) an opportunistic infection. 28/60 (46.7%) were asymptomatic at initiation. The initial ART regimens included 29 (61.7%) AZT/3TC/EFV; 7 (14.9%) AZT/3TC/LPV/r; and 4 (8.5%) DDI/3TC/NVP.The overall follow-up rate with the case managers at 8 months was 54/60 (90.0%). 40 subjects (66.7%) attended all of their ART clinic appointments Group 1); 13 (21.7%) were partially compliant to their ART clinic appointments (Group 2), including 6/13 (46%) who attended at least 90% of their clinic appointments; and 7 (11.7%) stopped attending their appointments (and receiving ART) on their own prior to the end of the 8 month follow-up period (Group 3)  attended at least one session and the median number of sessions attended by these 24 was 2. Table Overall, 31/60 (51.7%) were active IDU at enrollment and 27 (45.0%) were active at their last follow-up visit. However, among the 29 (48.3%) subjects who were drug free at enrollment, 7 (24.1%) relapsed and were active users at their last visit. Overall, 33/60 (55.0%) were drug-free at the last follow-up visit.Figure Intensive case management for HIV infected IDU is feasible and can be an effective complement to improve HIV treatment outcomes, including retention and adherence in Russia. The majority (90%) of participants enrolled in this pilot study remained in research follow up until the end of the 8 month project period and 74% had a viral load <1000 copies/mL at their last visit. This is a significant improvement compared to historic data where only 40% of IDU starting on ART in St. Petersburg were retained in care at 6 months, and comparable to the ART adherence performance in the US where, over a ten year period, 78% of patients achieved viral suppression 6 months after starting combination ART . AlthougBecause no substitution therapy is available in Russia, the options for substance abuse treatment are limited. Short-term detoxification is notoriously ineffective and psychological counseling without replacement therapy also has an extremely high relapse rate. Naltrexone, an opioid antagonist reduces relapse in Russia ,34 but iThe HIV/AIDS epidemic in Russia parallels the epidemic of drug use in Russia. The majority of participants in our cohort began injecting drugs when they were less than 20 years of age and have now been IDUs for at least 10 years. Many of this initial cohort of drug users who are still alive, now require ART. However, the success of the ART program will be hampered by continued drug use and no widely accessible and effective substance abuse treatment program.A comprehensive, multidisciplinary approach to care for HIV infected IDU has proven effective in other settings -37. In BThe limitations of our feasibility study include the small numbers of IDUs followed, no real- time comparison group that limited our ability to determine effectiveness, and questions about scaling up such a labor intensive case management system. Though feasible for a limited number of IDU, its unlikely that the resources would be available to scale up such an intensive program. A less intensive case management intervention would be sustainable and scalable. We believe the “supporter” support system could be retained within this system, but we do not know how fewer case manager contacts with the case and their supporter would affect the outcomes. Enhancing the use of cell phone technology would be one way to reduce the cost per case managed.Overall, intensive case management for IDU on ART is a feasible and promising strategy to enhance substance abuse and ART treatment in Russia. A case management system provides both individual and public health opportunities for prevention activities. Comprehensive prevention packages that coordinate substance abuse and HIV prevention strategies using case management as the cornerstone for HIV positive and HIV negative IDU, with appropriate replacement therapy, will be essential to improving substance abuse and HIV outcomes.None of authors have financial or non-financial competing interests.AVS contributed to the study design, coordinated all study procedures and drafted the manuscript. RVS participated in the study design, data collection and statistical analysis. IFH contributed to the study design, protocol development, data analysis and writing the manuscript. LBB participated in statistical analysis and preparation of the first draft of manuscript. VNE contributed to data analysis and logistic. APK contributed to logistic and study management. All authors read and approved the final manuscript.


The regimen was defined as at least 3 antiretroviral drugs with at least 2 nucleoside-reverse transcriptases (NRTIs) and either of at least one protease inhibitor (PI) or non-nucleoside-reverse transcriptases (NNRTIs). We categorised cART regimens as: NRTIs as tenofovir based or not; NNRTIs as nevirapine or efavirenz (but not both); and PI as atazanavir based or not. We found that the impact of various antiretroviral regimens on lipids in Asian and Australian cohorts was only different by cohort for total cholesterol (P for interaction between regimen and cohort: <0.001) but not in case of other lipids (P for interaction: >0.05). The differences in total cholesterol were however small and unlikely to be of clinical significance. Overall, tenofovir with nevirapine or atazanavir was associated with the most favorable lipids, while the PI regimens without tenofovir and atazanavir were associated with least favorable lipids. We conclude that the impact of various ART regimens on lipids is largely similar in Asian and Australian cohorts and that the newer drugs such as tenofovir and atazanavir are likely to provide similar benefit in terms of lipid profiles in both populations.We explored the mean differences in routinely measured lipids  according to exposure to different combination antiretroviral regimens in Asian ( Combination antiretroviral therapy (cART) for HIV infection is associated with adverse changes in lipid profiles and can include elevation in total cholesterol and triglycerides, which may increase the risk of coronary heart disease (CHD) –4. MoreoDrugs such as TDF, EFV, and ATV are becoming increasingly available in low-middle-income countries, including Asia , 10. HowObservational cohort studies can complement information from clinical trials, and allow us to examine the effects of art medications in the context of combination regimens, as opposed to head-to-head comparisons of selected drugs in clinical trials. In the present study, we aim to compare the relative impact of various cart regimens on lipid profiles in Asian and Australian cohorts using data from the treat Asia and the Australian HIV observational databases , which are formed on similar methodology and are known to be predominantly Asian and Caucasian, respectively .TAHOD and AHOD are clinical cohort studies of HIV-infected patients in Asia and Australia, respectively, and are part of the International Epidemiologic Databases to evaluate AIDS initiative. Both cohorts have similar methodologies, which have been previously published , 16. BriEthical approval for both the cohorts was obtained from the University of New South Wales, Sydney, Australia, and all other relevant institutional review boards. Data for both TAHOD and AHOD are transferred electronically to the Kirby Institute twice per year and include the same set of core variables. All data are subject to standardized quality control procedures.The outcomes of interest were mean (i) total cholesterol, (ii) triglycerides, (iii) high-density lipoprotein cholesterol (HDL-C) measured in mmol/L, and (iv) total cholesterol : HDL-C ratio. Lipid values are measured according to the local sites' standard of care in each cohort, and when measured, are captured during routine data transfer. TAHOD only records fasting lipids. In AHOD, both fasting and nonfasting lipids along with the fasting status are recorded. Further details of laboratory standards and methods at each site were not available.Data collection on lipid profiles started later in AHOD , compared to TAHOD . The lipid values before starting cART  were not available in most patients, and therefore changes from pre- to post-cART were not analysed. Mean lipid measurements were compared by different regimens and cohort.The cART regimen variable was defined as a regimen containing at least 3 antiretroviral drugs, including at least two NRTIs and either of at least one PI or an NNRTI. In order to evaluate the net effect of a combination regimen, rather than that of a single drug or a class, we defined eight mutually exclusive regimens. We categorised cART regimens as: NRTIs as TDF based (NRTIs + TDF) or not (NRTIs); NNRTIs as NVP or EFV (but not both); and PI as ATV based (PI + ATV) or not (PI).Based on these categories, the following mutually exclusive regimens were defined: (i) NRTIs (+TDF) + NVP; (ii) NRTIs (+TDF) + EFV; (iii) NRTIs + NVP; (iv) NRTIs + EFV; (v) NRTIs (+TDF) + PIs (+ATV); (vi) NRTIs (+TDF) + PI; (vii) NRTIs + PI (+ATV); (viii) NRTIs + PI. In all analyses, regimen (i) NRTIs (+TDF) + NVP was used as the reference group, as this regimen was thought to have the most favourable impact on lipids.Patients from TAHOD and AHOD were eligible for inclusion in the analysis if they started cART and had at least one lipid measurement within the first 24 months of cART commencement. Time at risk was defined as time spent on any of the regimens described previously and risk time started from the commencement of that regimen. Follow-up was censored at first of 24-month exposure to regimen of interest, date of death, loss to follow-up, or 31 March, 2010. Lipids values measured at the 6-monthly intervals in the first 24 months of start of cART were used. Thus each patient on each regimen could have up to 4 measurements . If more than one measurement was available in a given interval, one measured earliest in the given interval was used in the analysis. Intermittent changes in therapy including stopping part or all of a regimen for less than 14 days were not considered a stop in time at risk for that regimen. Each patient could contribute data to more than one regimen.a priori confounders were included in all models:The following fixed variables: cohort (TAHOD/AHOD), gender, HIV transmission group , IDU ± heterosexual, heterosexual, and other), and hepatitis B and C coinfection ;μL); HIV RNA viral load ; and body mass index (BMI) ;variables measured closest to the start of each cART regimen within past 6 months to 1 month after the start of the regimen of interest: CD4+ T-cell count . Since all lipid parameters were normally distributed with minimal skewness, data were not transformed. Separate models were fitted for each outcome. All models included time on regimen with lipid data, categorised as 6 monthly intervals. The interaction between the regimen and the cohort variables was assessed for each outcome. We also conducted the following sensitivity analyses: (i) restricting AHOD data to only lipid values which were documented to be taken as fasting in AHOD, (ii) excluding patients with missing BMI data, (iii) including only those with known Caucasian ethnicity in AHOD, and (iv) additional adjustment for stavudine (d4t) use in the multivariable model, as it was more common in TAHOD than AHOD.Data were analysed using STATA version 10 .There were 2845 participants (2051 in TAHOD and 794 in AHOD) who met the inclusion criteria. In TAHOD, 736 (35.9%) were Chinese, 654 (31.9%) were Thai, 152 (7.4%) were Cambodian (Khmer), 100 (4.9%) were Japanese and 62 (3%) were Indian. There were a total of 7897 total cholesterol values (5602 in TAHOD and 2295 in AHOD), 7293 triglyceride values (5002 in TAHOD and 2291 in AHOD), and 4669 HDL-C values (2949 in TAHOD and 1720 in AHOD). The frequency of total cholesterol measurements by regimen and cohort is shown in Patients contributed data to the median of 1 regimen (range: 1 to 4) with a median of 2 lipid measurements (IQR: 1–4) per patient. All measures of CD4 cell count, HIV viral load, and BMI were collected within 35 days of commencing the different ART regimens. Participants from TAHOD were more likely to be younger and female and have heterosexually acquired infection, hepatitis B coinfection, detectable HIV VL, lower median CD4+ count, shorter time spent on cART, lower BMI, lower mean total cholesterol, and higher HDL-C than those from AHOD . Also a P < 0.001, test for interaction). Overall, the mean total cholesterol was slightly lower for TAHOD participants, compared to AHOD participants, after adjustment for demographic and HIV-related characteristics, in most of the regimens   for triglycerides, HDL-C, and total cholesterol: HDL-C ratio. There was no significant interaction between cART regimen and the cohort type . Other regimens were not significantly different to the reference regimen.Forty-five percent of all of the AHOD measurements were taken fasting. Ethnicity was known in AHOD in 80% of participants, of whom greater than 80% were Caucasian. All of the sensitivity analyses, except for exclusion of missing BMI data, yielded very similar results, in terms of direction of effect, magnitude, and significance, as those from full analyses (data not presented). Since BMI was missing in a significant proportion of participants in both cohorts , restricIn this study, we examined the mean differences in lipids between various cART regimens in TAHOD and AHOD cohorts. We found that the relationship between regimen and lipids differed by cohort only in the analysis of total cholesterol level. For total cholesterol, the magnitude of effect of regimen differed between cohorts such that TAHOD participants tended to have slightly lower total cholesterol for most regimens (most notably for the NRTIs (+TDF) + PI (+ATV) and the NRTIs + PI regimens). Overall, we found that the NRTIs (+TDF) + NVP and the NRTIs (+TDF) + PI (+ATV) regimens were associated with the most favorable lipid profile, whereas the NRTIs + PI and the NRTIs + EFV regimens were associated with the least favorable lipid profiles.These regimen/lipid association findings are consistent with the literature from Western countries –8, 17. TThe observed differences in mean total cholesterol between TAHOD and AHOD cohorts, though statistically significant, were of small magnitude. The differences could be due to variations in race/ethnicity or dietary, environmental, and lifestyle factors . The cliThere are further limitations to this study. We divided each class of ART according to those shown to have favorable impact on lipids, that is, TDF, ATV, and NVP , 7, 8. HStrengths of our study include TAHOD and AHOD being founded on similar methodology thereby reducing the likelihood of confounding due to methodological differences. Also, the large sample size available allowed us to analyse several regimens, including those with TDF and ATV, which are less frequently used in low-middle income countries . MoreoveIn summary, our findings suggest that the impact of various ART regimens on lipids is largely similar in TAHOD and AHOD cohorts and that the newer drugs such as TDF and ATV are likely to provide similar benefit in terms of lipid profiles in both populations. We also found that TAHOD participants may have slightly lower mean total cholesterol for most regimens, although the clinical significance of this difference is uncertain. These findings contribute to the gap in evidence from Asian settings. Future studies should report pre- to post-ART monitoring of lipids and information on Framingham risk score in diverse populations.


Good adherence to antiretroviral therapy (ART) is critical for successful HIV treatment. However, some patients remain virologically suppressed despite suboptimal adherence. We hypothesized that this could result from host genetic factors influencing drug levels.CYP2B6) and LPV/r clearance . Viral suppression was defined as having HIV-1 RNA <400 copies/ml throughout the study period.Eligible individuals were Caucasians treated with efavirenz (EFV) and/or boosted lopinavir (LPV/r) with self-reported poor adherence, defined as missing doses of ART at least weekly for more than 6 months. Participants were genotyped for single nucleotide polymorphisms (SNPs) in candidate genes previously reported to decrease EFV  and 69 on LPV/r (38 suppressed and 31 not suppressed) were eligible. The poor adherence period was a median of 32 weeks with 18.9% of EFV and 20.3% of LPV/r patients reporting missed doses on a daily basis. The tested SNPs were not determinant for viral suppression. Reporting missing >1 dose/week was associated with a lower probability of viral suppression compared to missing 1 dose/week (EFV: odds ratio (OR) 0.11, 95% confidence interval (CI): 0.01–0.99; LPV/r: OR 0.29, 95% CI: 0.09–0.94). In both groups, the probability of remaining suppressed increased with the duration of continuous suppression prior to the poor adherence period .The investigated genetic variants did not play a significant role in the sustained viral suppression of individuals with suboptimal adherence. Risk of failure decreased with longer duration of viral suppression in this population. High level of adherence to antiretroviral therapy (ART) is needed to achieve and maintain virological suppression, prevent drug resistance and improve survival in HIV-infected individuals CYP2B6 (CYP2B6*6). Individuals with the CYP2B6 516TT (homozygous loss of function) genotype had higher efavirenz levels compared to carriers of 516GT (heterozygous loss of function) or 516CC (homozygous reference) genotypes CYP2B6 genetic variants to efavirenz disposition was assessed in a pharmacogenetic- pharmacokinetic population analysis, and interestingly, explained half of the inter-individual variability observed with this drug Although nearly perfect adherence to ART is critical for successful HIV treatment, some patients remain suppressed despite poor adherence. The ability to achieve and sustain virological suppression despite suboptimal adherence could result from host genetic and/or pharmacological factors. In fact, the administration of standard doses of most antiretroviral drugs results in a large inter-individual variability in plasma drug concentrations We used the longitudinal nature of the Swiss HIV Cohort Study (SHCS) to select individuals with long periods of self-reported poor adherence to HIV therapy and to investigate the genetic and pharmacological characteristics in those remaining suppressed compared to those not suppressed.www.SHCS.ch) This study included HIV-infected patients enrolled in the SHCS, a nationwide prospective cohort study enrolling HIV-infected individuals aged 18 years or older who are followed-up in HIV clinics  SLCO1B1*5; rs6945984 in CYP3A and rs717620 in ABCC2) Genotyping of single nucleotide polymorphisms (SNPs) in candidate genes previously reported to decrease EFV  allele, 1 = Het-LOF (heterozygous loss of function) allele or Hom-LOF (homozygous loss of function) allele. For LPV/r, score groups were subsequently classified as: <2 LOF alleles or ≥2 LOF alleles for the combination of the 3 SNPs as done previously EFV and LPV/r drug levels were measured during therapeutic drug monitoring only in case of clinical indication and therefore were either not available or regularly documented in all patients. Due to the limited number of drug levels measured within the poor adherence period, we considered all EFV or LPV/r levels available in a given individual. Drug levels are expected to be consistently higher in carriers of genetic variants thus making extrapolation a reasonable approach. Drug levels were quantified by liquid chromatography coupled to tandem mass spectrometry in accordance with previously validated methods th, 25th, 50th, 75th and 90th percentiles) were derived using simulations based on previously published population pharmacokinetic models Since plasma levels were measured at random time after last dose intake, observed EFV and LPV/r concentrations were categorized according to percentiles to allow for comparison between individuals. Concentration-time percentile curves  How often did you miss a dose of your medication in the last month? Daily, more than once a week, once a week, once every two weeks, once a month, never; and (ii) Did you miss more than one dose in a row? Yes, no. In this study, poor adherence was defined as reporting missing doses of medication either “daily”, “more than once a week”, or “once a week” on at least two consecutive reports. The poor adherence criteria were based on a previous analysis of the SHCS that showed a significantly higher risk of virological rebound in virally suppressed individuals reporting missing doses of ART≥once a week in the last month compared to individuals reporting never missing a dose of ART The primary endpoint of the study was virological suppression defined as having all HIV-RNA<400 copies/ml during the study period.Covariates that were potential confounders of the relationship between host genetic or pharmacological factors and viral suppression were considered for inclusion in the analysis: demographic-related factors , patient-related factors , condition-related factors , and treatment related-factors .Hepatitis B virus infection was considered active if HBs antigen or HBV DNA were positive. Hepatitis C virus infection was considered active if anti-HCV antibody and HCV RNA were positive and healed if HCV serology was positive and HCV RNA negative. Elevation of liver enzymes , aspartate aminotransferase (AST), alkaline phosphatase (ALP)) were graded according to the AIDS adverse event grading table.Logistic regression models were utilized to estimate the effect of host genetic factors and drug levels on viral suppression. Potential confounders of the relationship between host genetic and pharmacological factors were considered for inclusion in the multivariable model although the small sample size limited the number of variables. All analyses were carried out separately for EFV and LPV/r. Estimates of the association between the predictors and outcome are presented with odds ratios (OR) and 95% confidence intervals (CI).In sensitivity analyses, we also considered an alternative definition for viral suppression - all HIV-1 RNA<50 copies/ml.All analyses were done with SAS v 9.2  and Stata 10.1 .Over the 6.5 year study period, 648 poor adherence periods from 542 individuals were recorded. The patient selection process is depicted in In the EFV group, 28/37 (75.7%) maintained a viral load <400 copies/ml throughout the period of poor adherence. In the LPV group, only 38/69 (55.1%) of patients remained suppressed throughout the study period.CYP2B6 only for rs3745274 with an allele frequency of 25%. In the group of patients receiving LPV/r, genetic variants were found in SLCO1B1 (rs4149056), CYP3A (rs6945984) and ABCC2 (rs717620) with allele frequencies of 19%, 9% and 22%, respectively (www.ncbi.nlm.nih.gov/SNP).In the group of patients receiving EFV, genetic variants were found in ectively . OverallCYP2B6 and the likelihood of remaining suppressed . When analyzing the joint effect of the 3 SNPs in a genetic score, the univariable logistic regression showed a trend between a decreased likelihood of viral suppression in carriers of genetic variations (p = 0.08) however the trend did not remain in the multivariable analysis.Univariable and multivariable logistic regression analyses for LPV/r failed to detect an association between each independent SNP and viral suppression (p>0.15) with the exception of the univariable result for SLCO1B1*5 and higher drug levels  but not for carriers of variants in CYP3A (p = 0.63) and ABCC2 (p = 0.61).Drug concentrations were only available in 30% of EFV and 50% of LPV/r patients. For most patients, the intra-individual variability in drug levels was very pronounced further supporting the poor adherence pattern in this selected population. No association were found between higher drug levels  and presence of genetic variants in EFV patients (p = 0.36) or combined genetic variants in LPV/r patients (p = 0.26). The analysis of independent genetic variants in LPV/r patients showed a correlation between carriers of th percentile) was associated with a lower likelihood of viral suppression in LPV/r patients . Due to the small number of patients with available drug concentrations, drug levels were not included in the multivariable analyses.No association was found between higher drug levels and the likelihood of remaining suppressed in EFV (p = 0.54) and LPV/r patients (p = 0.12). However, single or repetitive exposure to low drug levels  . HoweverIn univariable models of LPV/r patients, having low adherence levels, past or current IDU, co-medication, mild elevation of ALP , or longer time since HIV diagnosis was significantly correlated with a decreased likelihood of remaining suppressed during the period of poor adherence. Prior suppression on the current regimen and higher baseline CD4 cell count were associated with an increased likelihood of remaining suppressed despite poor adherence . In multThese findings remained consistent when defining viral suppression as RNA<50 copies/ml.Nearly perfect adherence to antiretroviral therapy is widely accepted as the primary determinant for achieving and maintaining viral response. However, less is known about the determinants of virological suppression observed paradoxically in some individuals with long periods of self-reported poor adherence to ART. We hypothesized that individuals carrying genetic variants associated with a slow metabolizing profile would maintain sufficient viral inhibitory drug levels even after missing doses.CYP2B6 and the likelihood of remaining suppressed in patients with self-reported suboptimal adherence to EFV based regimens. The population pharmacokinetic estimates of EFV half-lives have been reported to be 23, 27 and 48 hours for individuals with the CYP2B6 516 GG, GT and TT genotypes, respectively CYP2B6 516 GG (53%) and 516 GT genotypes (44%) whereas only one patient had the 516 TT genotype  as indicated by the increased risk of viral failure in patients missing more than 1 dose a week compared to those missing 1 dose a week  and 4. TBesides the degree of adherence, we found that the likelihood of remaining suppressed was also dependent on the dosing schedule for LPV/r. In our population, LPV/r was administered twice daily (BID) in 64 patients and once daily (QD) in 5 patients. Interestingly, the failure rate was higher in those on a QD regimen with 80% (4/5) of the patients on the LPV/r QD regimen compared to 42% (27/64) on the LPV/r BID regimen not maintaining viral suppression. This observation is compatible with the findings of a recent study comparing the pharmacokinetics of LPV/r BID and QD following drug cessation Interestingly, our data showed that the probability of remaining suppressed increased with the duration of continuous suppression prior to the poor adherence period in both groups, which is in agreement with previous data Some limitations of our study should be acknowledged. The stringent selection criteria of our study population (severe non adherence and being steadily on EFV and/or LPV/r) gave us a small sample size and limited power to explore associations in our data. In addition, the limited number of patients with documented drug levels did not allow satisfactory exploration of the role of drug concentration as a predictor of viral suppression. Although, due to the high level of non-adherence, this relationship may have been difficult to quantify precisely.The investigated genetic variants did not play a significant role in the sustained viral suppression of individuals with poor adherence. The risk of virological failure decreased with longer duration of viral suppression in this selected population. Patients varied considerably in their prior ART exposure and, although we attempted to adjust for this and the possibility of resistance, we cannot exclude the potential impact of these factors.


We already reported good virological and immunological responses after 1 to 4 years in cohorts of patients on 1st line and more recently, among an Esther cohort of 70 patients after 2 years on LPVr-based 2nd line regimen. However, emergence of LPV resistant associated mutations is becoming a major concern in low and middle income countries.By the end of 2009, the number of HIV-1 infected patients on RTI-based 1nd line regimen in Cambodia.This study aimed to describe the resistance pattern of both the protease (PR) and integrase (IN) coding regions in HIV-1 CRF01-AE infected patients failing LPV-based 2nd line regimen in Cambodia.Analysis of the Protease and Integrase drug resistance genotyping of 95 HIV-1 strains infected patients presenting detectable viral load on LPV/r-based 210 copies/ml [IQR: 2.8-3.4]). The 77 other CRF01_AE strains, harbored polymorphism mutation in position M36, H69 and L89 conferring possibly resistance to TPV/r. Forty-nine (median VL: 5Log10 copies/ml [IQR: 4 - 5.5]) did not present any other PI associated resistance mutation. In contrast, 28 patients showed multiple resistances to PI. The median duration on LPV/r regimen was 34.5 months [IQR: 23.5 – 53.3] and the median VL was 5Log10 copies/ml [IQR: 4.3-5.6]. Twenty-five patients were resistant to LPV/r (7 possibly resistant). Twenty-seven were resistant to IDV, 21 and 19 to ATV/r and FPV/r, respectively. Twenty-five were resistant to NFV (10 possibly), 22 resistant to SQV/r (9 possibly). Seven showed resistance to DRV/r (5 possibly). Finally, excluding possible resistance, 21/28 (75%) was resistant for at least 3 PIs. Clinical investigation revealed that most of these 28 patients starting several RTIs and PIs early around 2000. All of them were sensitive to raltegravir, elvitegravir (integrase inhibitors), and etravirine (Non-Nucleoside reverse transcriptase inhibitorse).Lack of amplification in PR gene was observed for 18/95 presenting low viral load  of Cambodian patients presenting detectable viral load on LPV/r–based 2


The absence of detectable HIV resistance after treatment failure may result from non-adherence, especially for drugs such as ritonavir-boosted PIs (PI/r) for which minimum adherence may be sufficient to achieve suppression. This analysis aimed to investigate the association between adherence, indicated by a detectable PI plasma concentration, and development of PI resistance in patients presenting with virological failure of a PI/r regimen.Patients were included if they had virologically failed a PI/r, defined as a viral load (VL) >1000 copies/mL after ≥4 months continuous exposure to a PI/r and with a plasma sample available within 1 month of the estimated VL failure date. Samples were analysed for PI levels by a validated reversed-phase HPLC method; an undetectable PI level was defined as below the PI-specific lower limit of detection. Genotypic sequencing was also carried out retrospectively on the identified sample for those with no previous PI failure and PI resistance was defined as the presence of ≥1 major PI mutation (IAS-USA). Logistic regression was used to assess risk factors for an undetectable PI level and for detection of PI resistance at VL failure using exact methods for small datasets.3 and median VL was 4.8 log10copies/mL. 43 patients (51%) had an undetectable PI level at time of VL failure and were similar to those with detectable levels in terms of demographics, ARV history and previous VL failure. However, injecting drug use was associated with a greater risk of undetectable PI level (univariate odds ratio (OR) IDU vs. not: 3.7; 95% CI: 1.1-12.5; p=0.038).85 patients were included. PI/r regimens were started in Sept 2002 (median) with VL failure occurring a median time of 17 months later. At time of starting the PI/r (baseline), 57% were ARV-naïve, median CD4 count was 217 cells/mm44 (52%) of the 85 patients were successfully tested for resistance and had no previous PI failure. Those with undetectable PI levels were significantly less likely to have PI resistance  than those with detectable levels , exact median unbiased estimate of OR: 0.1; p=0.029. Baseline VL, CD4 count, demographic and ARV-related variables were not associated with PI resistance due to limited power in this dataset.Non-adherence to a PI/r regimen, as measured by an undetectable PI level is linked to a lower rate of detection of PI resistance at time of VL failure.


Current guidelines recommend three drug combinations to treat antiretroviral naïve HIV-infected patients; some data of novel strategies with NRTI-sparing regimen in this setting are now available ,2. The sThis is an ongoing, proof-of-concept, randomized, open-label, 48 weeks trial. Data were collected at baseline (BL) and at 4, 12 , 24, 36 and 48 weeks. Comparisons between groups evaluated by the chi-square or Mann-Whitney rank-sum test. Results reported as median (Q1-Q3) or frequency (%), as appropriate.10 copies/mL. No difference in BL characteristics were found between the two treatment groups.Up to date, 13 pts  reached week 24 (W24), 10  week 12 (W12), 1(MVC) week 4 (W4) without modification of the initial regimen; age 41.1 (41.7-49.9) years, 1/24 (4%) female, infected since 3.8 (2.3-7.6) years, CD4 nadir 266 (240-321) cells/µL. At BL: CD4 284 (260-325) cells/µL; CD4% 17.6 (13.9-22.5), HIV-RNA 4.3 (3.9-4.9) logAt W24, all patients in both groups had HIV-RNA<50 copies/ml; decrease in viral load was similar in both groups at each timepoint. CD4 cells count increased in both groups, more rapidly in MVC group and was similar at week 12 and week 24, possibly due to the small number of subjects .Treatment was well tolerated, without grade 3 or 4 adverse events. No significant differences between the two groups were observed in bone marrow function, AST, ALT and CPK values, creatinine value, glucose profile (fasting glucose and insulin) and lipid profile  expect for triglycerides that significantly increased in TDF/FTC group .In this small sample size, NRTIs-sparing regimen with Maraviroc QD and lopinavir/ritonavir is similar in efficacy and tolerability to conventional treatment in naïve-patients. A more favourable trend in immunological recovery was observed but it needs to be confirmed in larger samples. Regimens NRTIs-sparing in HIV-infected patients naïve to antiretroviral therapy should be explored.