To assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients.3 received standard 6-month tuberculosis treatment and antiretroviral therapy including a daily-dose of 600 mg of efavirenz, irrespective of their body weight. Mid-dose blood samples were drawn both on tuberculosis treatment  and off tuberculosis treatment (week 50 of follow-up). Considered therapeutic range was 1,000 to 4,000 ng/mL. Multivariate analysis was performed to evaluate the association between efavirenz concentration below 1,000 ng/mL and virological failure. Linear regression was used to test the association between efavirenz exposure and CD4+ T cell gain. Severe side effects potentially related to efavirenz were described and their association with efavirenz exposure was tested by multivariate analysis.HIV-infected adults with CD4+ T cell count ≤200/mmEfavirenz plasma concentrations were available in 540 patients. Median [interquartile range] efavirenz concentrations were 2,674 ng/mL , 2,667 ng/mL  and 2,799 ng/mL  at week +2, week +6, week 22, respectively, and 2,766 ng/mL  at week 50. Efavirenz concentrations were lower at week 50 (off rifampicin) compared to week 22 (on rifampicin) (p<0.001). Late attendance to study visit and low hemoglobinemia were the only factors associated with an increased risk of efavirenz concentration below 1,000 ng/mL. Efavirenz concentration below 1,000 ng/mL was not associated with treatment failure. Efavirenz concentration above 4,000 ng/mL was associated with higher risk of central nervous system side effects (p<0.001) and of hepatotoxicity (p<0.001).Body weight and tuberculosis treatment were not associated with low efavirenz concentrations or treatment failure, supporting the 600 mg daily-dose of efavirenz in HIV-tuberculosis co-infected patients. High efavirenz concentrations were related to a higher risk of central nervous system side effects and hepatotoxicity.NCT01300481ClinicalTrials.gov  Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) widely used in combination with nucleoside reverse transcriptase inhibitors as first-line treatment of HIV-1 infection. Concomitant administration of antiretroviral therapy (ART) and rifampicin - a potent inducer of drug metabolizing enzymes - is challenging due to drug-drug interactions The CAMELIA (ANRS 1295-CIPRA KH001) randomized clinical trial showed a 34% reduction of mortality in severely immunocompromised HIV-infected adults treated for tuberculosis when efavirenz-containing ART was initiated two weeks compared to eight weeks after tuberculosis treatment onset The protocol of the CAMELIA trial and the TREND statement check list of this longitudinal pharmacological study are available as supporting information; see CAMELIA The CAMELIA trial was approved by the Cambodian National Ethics Committee and by the Institutional Review Boards of the Immune Disease Institute of Harvard Medical School and Médecins Sans Frontières. This trial was conducted in accordance with the Declaration of Helsinki 3 and newly diagnosed, smear-positive tuberculosis who were recruited in CAMELIA and followed in five Cambodian hospitals from 2006 to 2010, we conducted a longitudinal pharmacological study in some of them. Tuberculosis treatment consisted of a six-months regimen containing rifampicin (8–10 mg/kg/day), isoniazid (4–5 mg/kg/day), ethambutol (15–20 mg/kg/day) and pyrazinamide (20–30 mg/kg/day) as fixed dose combination (FDC) for the first two months, followed by rifampicin (8–10 mg/kg/day) and isoniazid (4–5 mg/kg/day) as FDC for the next four months. In the CAMELIA trial, patients were randomized to initiate ART either two weeks (“early-ART” group) or eight weeks (“late-ART” group) after onset of tuberculosis treatment. ART consisted of lamivudine (150 mg) and stavudine (30 mg) twice daily and efavirenz 600 mg once daily in the evening, irrespective of patients' body weight.Main characteristics of enrolled patients and trial design have been described elsewhere To account for the differential timing of ART initiation in the two study arms, blood samples for determination of plasma efavirenz concentration were drawn two weeks (W+2) and six weeks (W+6) after ART initiation for all patients, corresponding to four and eight weeks after tuberculosis treatment onset in the early-ART group, and 10 and 14 weeks after tuberculosis treatment onset in the late-ART group. Follow-up blood samples were also drawn at week 22 and week 50 after tuberculosis treatment onset in both groups. At this latter time point, patients received efavirenz without concomitant tuberculosis treatment Figure 1Blood samples were collected early in the morning on EDTA tubes 14±2 hours after efavirenz intake and reflected mid-dosing plasma concentrations Virological efficacy of ART was assessed at week 8 in patients from the early arm and at week 26 and week 50 for all patients. It was described as the proportion of patients with undetectable plasma HIV RNA (<250 copies/mL). CD4+ T cell gain since ART initiation at week 26 and week 50 was considered for immunological reconstitution in all patients. Clinical or biological adverse events were reported and graded by on-site investigators using the Division of AIDS table for grading the severity of adults and pediatric adverse events Efavirenz plasma concentrations on and off rifampicin-based tuberculosis treatment were described as median and inter quartile range [IQR] and were compared at two consecutive time-points using paired Wilcoxon tests. Factors associated with efavirenz concentration below 1,000 ng/mL were identified using a mixed effect logistic regression to account for multiple measurements within patients. The main exposure variables were concomitant tuberculosis treatment and patients' body weight at the time of sampling.We evaluated the association between plasma concentrations of efavirenz and: i) virological efficacy, defined as a viral load <250 copies/mL at week 8 (only considering patients from the early arm), week 26 and week 50 of follow-up, using a logistic regression; ii) immunological efficacy, defined as the CD4+ T cell gain at week 26 and week 50 of follow-up, using linear regression models; and iii) occurrence of adverse events before week 58 of follow-up using a logistic regression. Only plasma concentrations of efavirenz prior to the evaluation time were considered. The threshold in efavirenz concentrations was 1,000 ng/mL for the association with virological and immunological efficacy, and 4,000 ng/mL for the association with occurrence of adverse events. Other factors considered in all these analyses were the study site, CAMELIA study arm, gender, age at enrolment, body mass index (BMI) and body weight as recorded at ART initiation and sampling time, tuberculosis location, occurrence of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS), as well as biological factors measured at ART initiation  and/or at the sampling time .In all analyses, factors associated with a p-value <0.20 in univariate analysis were entered in the multivariate model. Factors independently associated with the outcome were then identified using a stepwise backward procedure based on the Wald test. Two-sided hypotheses and tests were adopted for all statistical inferences, a p-value <0.05 being considered statistically significant. All statistical analyses were performed using STATA 11 software .. Characteristics of the patients at ART initiation are displayed in . Patients were at an advanced AIDS stage with a median [IQR] CD4+ T cell count of 25 cells/mm3 [12–60] and median [IQR] BMI of 17.3 kg/m2 [15.8–19.1]; 167 patients (31%) had a body weight ≥50 kg, including 27 (5%) patients weighing ≥60 kg. The number of patients with body weight ≥50 kg increased during the study, reaching 261 (58.1%) and 277 (68.7%) at week 22 and week 50, respectively. The number of patients with body weight ≥60 kg also increased reaching 58 (12.9%) and 85 (21.1%) at week 22 and week 50, respectively.Among the 661 patients enrolled in the CAMELIA trial, 540 were considered in this analysis. The remaining 121 patients were not included for various reasons shown in A total of 1,759 efavirenz concentration measurements were available. Of the 540 patients, 430 (80%) had at least three efavirenz concentrations available and 401 (74.3%) had samples on and off concomitant tuberculosis treatment. A total of 40% of samples were drawn when the patients were taking rifampicin and their body weight was ≥50 kg and 8% were drawn when body weight was ≥60 kg.In the presence of rifampicin-based tuberculosis treatment, median [IQR] efavirenz concentrations were 2,674 ng/mL , 2,667 ng/mL  and 2,799 ng/mL  at W+2, W+6 and week 22, respectively. At week 50, six months after the end of tuberculosis treatment, efavirenz concentration was 2,766 ng/mL  Figure 3. Efavirenz concentration was persistently within the therapeutic range in 243 patients (45.0%). At W+2, W+6 and week 22, while receiving rifampicin-based tuberculosis treatment, 44 (9.7%), 24 (5.3%) and 15 (3.3%) patients had efavirenz concentrations below 1,000 ng/mL. Off tuberculosis treatment at week 50, 12 (3.0%) patients had efavirenz concentrations below 1,000 ng/mL. The proportion of efavirenz concentrations below 1,000 ng/mL was not different on and off rifampicin-based tuberculosis treatment when comparing data collected at weeks 22 and 50 (p = 0.76). Nine (1.7%) patients had all measured concentrations below 1,000 ng/mL with an efavirenz concentration of 643 ng/mL [111–756], 829 ng/mL [828–904], and 825 ng/mL [204–915] at W+2, W+6 and week 22, respectively. These nine patients did not have efavirenz concentration available at week 50. Among them, two patients died after two and three months of follow-up, respectively, two received a non efavirenz-based regimen at week 50 and five did not have a sample drawn at this time. A total of 89 patients (16.3%) had all concentrations above 4,000 ng/mL: efavirenz concentration was 8,740 ng/mL , 10,563 ng/mL , and 11,465 ng/mL  at W+2, W+6 and week 22, respectively. In these 89 patients, there was a significantly lower efavirenz concentration at week 50  compared to the previous concentration at week 22 (p<0.001) (The distribution of efavirenz plasma concentration per sampling week is displayed in p<0.001) Figure 53 and 165 (108–226) cells/mm3 at W26 and W50, respectively. Similarly, having at least one efavirenz concentrations below 1,000 ng/mL prior to the immunological evaluation time was not associated with a lower CD4+ T cells gain at week 26 or week 50 .At week 8 , week 26 and week 50, 206 (74%), 455 (91%) and 458 (97%) patients had plasma HIV RNA concentration <250 copies/mL, respectively. Patients with at least one efavirenz concentration below 1,000 ng/mL prior to the virological evaluation time did not present a lower risk of virological success at these three time-points than the other patients ]: 0.80 [0.35–1.86], 0.31 [0.07–1.32] and 1.37 [0.38–4.94] at weeks 8, 26 and 50, respectively). Efavirenz concentrations measured in 27 and 58 patients weighing ≥60 kg at W+6 and week 22 were all above 900 ng/mL and were not associated with virological failure at week 26 . The median [IQR] CD4+ T cells gain from baseline was 110 (69–168) cells/mmDuring the trial, 55 (10.2%) patients experienced 55 severe (grade 3–4) adverse effects, including: 47 hepatotoxicity (85.5%); five CNS events (9.1%) -including two depressions, two deliriums and one insomnia-; three mucocutaneous events (5.4%). Overall, 23 CNS side effects of all grades were observed in 22 patients. They included sleep disorders (57%), depression (17%), vertigo (13%) and delirium (13%). One patient with severe depression committed suicide at 40.5 weeks of follow up. Efavirenz concentrations of this patient reached 13,462 ng/mL at W+6 and 25,780 ng/mL at W22.The risk of experiencing a severe adverse effect was not significantly increased in patients who had efavirenz concentrations that was at least once above, or always above 4,000 ng/mL, when compared to patients who never had concentrations above 4,000 ng/mL (p = 0.30). However, the risk of developing a CNS side effect, irrespective of the severity, was significantly increased in patients who had efavirenz concentrations at least once above 4,000 ng/mL or those with concentrations always above 4,000 ng/mL, compared to patients who never experienced efavirenz concentrations above 4,000 ng/mL . The risk of developing hepatotoxicity of any grade was higher in patients with concentrations always above 4,000 ng/mL . However, having intermittent efavirenz concentrations above 4,000 ng/mL did not increase the risk of hepatotoxicity and even decreased the risk .Efavirenz plasma concentrations on and off rifampicin-containing tuberculosis treatment were documented in more than 500 Southeast Asian patients co-infected with HIV and tuberculosis from Cambodia. Our CYP2B6 516TT genotype had a 3.5-fold increase in efavirenz exposure CYP2B6 516 T is 34% in Cambodian population, higher than in Caucasian population, this could at least in part explain the high concentrations of efavirenz measured in our population The efavirenz concentrations measured in a Cambodian population after 600 mg daily efavirenz administration, are in keeping with those reported in studies conducted mainly in Caucasian and African American or African patients or in smaller cohorts of Thai patients A number of studies have been conducted to assess the effect of rifampicin or rifampicin based tuberculosis treatment co-administration on efavirenz concentrations, which reported results different from those reported here. Three studies with a small number of volunteers or patients showed that plasma efavirenz levels were decreased in the presence of rifampicin alone or rifampicin-based tuberculosis treatment Our findings in a large patient study show no significant reduction in efavirenz concentrations with rifampicin-based tuberculosis treatment co-administration irrespective of body weight, consistent with data from a recently published study et alOf note, late attendance to protocol visits was associated with a higher risk of efavirenz concentrations below 1,000 ng/mL and may be due to drug shortage between planned and actual protocol visits. However, sustained efavirenz concentrations above 600 ng/mL have already been reported in association with its long half-life (>24 hours) CYP2B6 metabolizer genotype - were likely to experience CNS toxicity High efavirenz plasma concentrations were associated with an increased occurrence of CNS side effects of all severity grades. It has been previously reported that up to 50% of patients receiving efavirenz - especially if they had a slow Depending on the considered studies, efavirenz plasma concentrations above 4,000 ng/mL were CYP2B6 G516T, which explained at least part of the large inter-individual variability of efavirenz concentrations, was not characterized in these 540 patients. Lastly, tolerance of efavirenz was not assessed by systematic questionnaires leading to potential under reporting of side effects. It could be argued that all effects reported in our study were representative of tolerance in real life situation. Although elevation of liver enzymes and hepatotoxicity were related to high efavirenz concentrations, efavirenz may not be the only associated factor. Tuberculosis treatment could favor transient liver toxicity and our one year study did not allow long term evaluation of efavirenz related hepatotoxicity. In addition, hepatitis C status of included patients was not recorded in the CAMELIA study. Our finding that CNS adverse effects were related to high efavirenz concentrations should favor initiation of clinical trials evaluating lower efavirenz dosing and the development of pharmacovigilance to carefully record adverse events occurrence in resource-limited countries.Our study presents some limitations. First, patients with a high body weight were not present in our study population, as only 27 patients at W+6 and 58 patients at week 22 had a body weight of 60 kg or above. Indeed high body weight is not common in Southeast Asia and in patients with such advanced disease presentation. However, efavirenz concentrations were not associated with virological failure (observed in 8%) at week 26 in these patients. Second, efavirenz pharmacokinetic characteristics were not fully characterized in our population. Mid-dose and not pre-dose trough concentrations were collected as a surrogate of efavirenz exposure. However, such approximation is acceptable as efavirenz has an elimination half-life longer than the 24 h-dosing interval, which would minimize fluctuations between peak and trough concentrations. In addition, the genetic polymorphism of In conclusion, our study provided efavirenz plasma concentrations in a large cohort of Southeast Asian patients receiving a daily standard-dose of 600 mg co-administered with rifampicin-based tuberculosis treatment. We found that efavirenz concentrations were in the same range than in other studies mostly conducted in African HIV-tuberculosis co-infected patients, demonstrating that rifampicin-based tuberculosis treatment does not impair efavirenz exposure and efficacy, irrespective of body weight. A proportion of patients with high efavirenz concentrations were at higher risk of CNS side events occurrence. Whether efavirenz dosing should be reduced in these patients to improve tolerance warrants further study.Checklist S1CONSORT Checklist.(PDF)Click here for additional data file.Protocol S1Trial Protocol.(PDF)Click here for additional data file.


There is an ongoing debate about when to use efavirenz (EFV) or nevirapine (NVP) for first line antiretroviral treatment (ART) in developing countries, fuelled by EFV's link with teratogenicity in rats and NVP's risk of hepatotoxicity with increasing CD4 levels and it's interactions with Rifampicin. This paper compares the effectiveness of these two drugs in a multicentre adult cohort of ART patients attending public health facilities in South Africa.A retrospective cohort analysis of routine data on 27350 ART naïve adults initiated between March 2004 and March 2007 at 56 public health sites across 4 provinces was completed. Stata 9 was used to conduct analyses which included Kaplan Meir survival analysis, logistic regression, generalised estimating equations and Cox proportional hazard models.Median follow up time was 9.3 months and median baseline CD4 count 113 cells/mL (IQR= 57-165). Multivariate analyses showed patients receiving first line regimens containing EFV to have been more likely to suppress virologically both at 6 months  and at any time between 6 and 36 months , less likely to change regimen  and more likely to die . A subset analysis of 18527 patients with pregnancy and tuberculosis status reported showed no difference in hazard rates for death between the two groups .This data shows superior results for patients on EFV with respect to all outcomes except death. Retrieval of missing data about pregnancy and tuberculosis status may push this last association toward the null. Protease inhibitors are an alternative to non-nucleoside reverse transcriptase inhibitors (NNRTIs) for first line use; but are currently too costly. There is an urgent need for further research into currently available NNRTIs; as well as the development of new antiretrovirals for resource depleted settings. In the interim the developing world needs to increase access and bring down the cost of existing drugs and implement more efficient treatment strategies.


Among all clients, similar proportions of refugee and host clients were <95 % adherent to pharmacy refills . When restricting to clients on treatment for ≥25 weeks, similar proportions from each group were not virologically suppressed . Refugee status was not independently associated with the outcome . Overall, the proportions of refugee and host community clients with unsuppressed viral loads and sub-optimal adherence were similar, supporting the idea that refugees in protracted asylum situations are able to sustain good treatment outcomes and should explicitly be included in the HIV strategic plans of host countries with a view to expanding access in accordance with national guidelines for HAART.In response to an absence of studies among refugees and host communities accessing highly active antiretroviral therapy (HAART) in urban settings, our objective was to compare adherence and virological outcomes among clients attending a public clinic in Kuala Lumpur, Malaysia. A cross-sectional survey was conducted among adult clients (≥18 years). Data sources included a structured questionnaire that measured self-reported adherence, a pharmacy-based measure of HAART prescription refills over the previous 24 months, and HIV viral loads. The primary outcome was unsuppressed viral load (≥40 copies/mL). Among a sample of 153 refugees and 148 host community clients, refugees were younger  contains supplementary material, which is available to authorized users. Global estimates suggest that 8 million people, or 54 % of 14.8 million who are eligible, receive highly active antiretroviral therapy (HAART) . Given pSungai Buloh Hospital, Kuala Lumpur, Malaysia was chosen as the study setting as it met our criteria of an urban, Southeast Asian setting, with sufficient numbers of refugees accessing HIV treatment and care services from a single point of care. At the start of the study (April 2010), 91,985 individuals were registered by the United Nations High Commissioner for Refugees (UNHCR) as refugees or asylum seekers in Malaysia, 315 had an HIV diagnosis, and 171 were on HAART. Over 98 % of refugees on HAART were from Myanmar. By the end of 2009, an HIV-positive refugee remained in Malaysia for an average of 3.7 years; 32 % were resettled to high-income countries after an average of 2.9 years . Malaysia has not signed the 1951 Refugee Convention and its 1967 Protocol; however, the Ministry of Health issued a circular in 2006 that permitted refugees to access public health services, including antiretroviral therapy (ART) as part of the national HIV treatment and program. Initially not included in national strategic plans [A 15-week (April–July 2010) cross-sectional survey, conducted at the Infectious Diseases Clinic, Sungai Buloh Hospital, aimed to recruit all refugees identified by UNHCR as recipients of HAART and a similar number of host community clients attending the same outpatient clinic. Clients were invited to participate if they were ≥18 years of age, on HAART for ≥30 days and gave informed consent. Refugees had routine access to the clinic one day per week, therefore we sought to recruit host community clients on only one other day per week. Those who met the inclusion criteria were recruited consecutively at the time of their regular clinic appointment and were re-contacted if they agreed but were unable to participate at the time of recruitment. In an attempt to obtain a complete sample, all eligible refugee clients on HAART who met the inclusion criteria but were not seen in the clinic during the study period were contacted by telephone or by a community representative. As attempts were made to recruit all refugees known to be on HAART, the number of eligible refugees determined the upward limit on sample size. Power calculations were initially completed using expected numbers of refugees on HAART and expected proportions virologically suppressed. Given a sample size ratio of 1:1, with 150 clients per group (representing 88 % of eligible refugees) and a level of viral suppression of 70 % in the refugee group, the study had an 80 % chance of detecting a 14 % prevalence difference as statistically significant at the 5 % level. Recruitment of the host community on a 2:1 basis lowered the detectable difference to 12 % (net efficiency gain = 14 %), therefore, the 1:1 strategy was considered sufficient for comparison. To assess the extent to which the host community sample was representative, a sampling frame was constructed from which a randomly selected comparison sample of 150 host clients was selected for the purposes of comparing basic demographic characteristics with the recruited sample.The primary outcome was unsuppressed viral load (≥40 copies/mL). Data sources included a structured questionnaire with self-reported adherence measures, a pharmacy-based measure of HAART prescription refills over the previous 24 months and HIV viral loads. The structured questionnaire was translated into Bahasa Malaysia, Tamil, Mandarin, Burmese, and Falam , then back-translated into English. The original and back-translated English versions were reconciled, then adjusted during pre-testing to enhance validity. Key self-reported adherence measures included a retrospective four-day dose-by-dose recall  and a rep < 0.1 in univariable analyses. A “self-change processes model” was fitted by adjusting each new factor by all retained treatment context factors, then adjusting again for any additional factors with p < 0.1. An “action state” model was fitted in a similar fashion but adjustment was restricted to factors from previous levels only so that collinear adherence measures would be excluded. The final regression model was obtained by excluding factors with the highest p value, sequentially, until all remaining factors met p < 0.05. Covariates of interest retained throughout the modelling process included refugee status, age, and time on HAART. Adherence factors were retained in the final model but were not adjusted for in order to avoid over-adjustment bias [Socio-demographic characteristics were compared between host and refugee groups using Mann–Whitney tests, chi-square or Fisher’s exact tests and chi-square tests for trend. Risk factors for unsuppressed viral load were evaluated using unconditional logistic regression; effect estimates were odds ratios (OR) and corresponding 95 % confidence intervals (CI). The order of entry of factors into the model was determined using a three-level, forwards, step-wise modelling approach drawing on social action theory  to groupent bias –15.Ethical approval was received by the Clinical Research Centre and the Medical Research Ethics committee in Malaysia  and the London School of Hygiene and Tropical Medicine Research Ethics Committee .N = 2,870) and was similar on most socio-demographic indicators to a randomly sampled host comparison group (Supplementary Table 1). Almost all (95 %) HIV-positive refugees accessing services from the study clinic were Burmese while the host community group was 61 % Chinese, 25 % Malay, and 15 % Tamil or other ethnic groups. The recruited refugee and host community groups were different on a variety of indicators (Table p < 0.001), had a higher proportion of women , a shorter median time on HAART , a shorter time since HIV diagnosis , and a lower most recent routine CD4 count . Among refugees, the median time of residence in Malaysia was 3.6 years  and the median time since having received formal refugee recognition was 1.8 years .We recruited 153 refugees and 148 Malaysian adults reflecting 90 % and 81 % participation rates (eligible clients who were seen or contacted and agreed to participate), respectively. The Malaysian group comprised 6 % of the target population of eligible clients , whereas the proportions who self-reported sub-optimal adherence on the one-month VAS were higher . The pharmacy refill results were also higher but similar in both groups . Within each group, there was evidence for ordered trends between self-reported measures of adherence and proportions not virologically suppressed among clients on treatment for ≥25 weeks. On the pharmacy refill measure, there was strong evidence for this trend among refugees, but this did not hold for the host community (see Supplementary Table 2).Viral load results indicated that 24 % (72/296) of clients had not achieved viral suppression (≥40 copies/mL). There was no difference between the proportions of refugees and host community clients who had not achieved viral suppression overall, or when restricting analyses to clients on treatment for ≥25 weeks .Unsuppressed viral load was defined as ≥40 copies/mL. In initial analyses of contextual factors (Table p = 0.009) and a harmful effect of having reported any treatment interruption in the past month , adjusting for age group, time on HAART, refugee status, sex, temporary travel in past year, time to clinic, time from diagnosis to HAART start and previous regimen switch.There was no evidence for associations between self-change process factors and the outcome Table . Among ep = 0.05), increasing time between diagnosis and treatment start  and adherence to pharmacy claim schedule  as protective, while temporary migration of ≥1 month in the past year  and average travel time to clinic of ≥1 hour  increased the odds of having an unsuppressed viral load. There was no evidence for an association between refugee status and unsuppressed viral load  adjusting for age group, refugee status, time on HAART, sex, temporary migration in the past year, average time to clinic, and time from HIV diagnosis to HAART start.The final multivariable model Table  identifiIn this study, the first we are aware of that investigated adherence and treatment outcomes by comparing refugees with a host community in an asylum setting, a minority of both refugee 19 %) and host community clients 16 %) on HAART for ≥25 weeks did not achieve viral suppression. Only minor differences were found on self-reported and pharmacy-based adherence measures. Adherence and virological outcomes were comparable to results from other Asian HIV clinics. In a multicentre prospective cohort carried out in 17 Asian settings, Oyomopito and colleagues found that 17 % were not virologically suppressed after 12 months on HAART  % on HAA found ad % and hoGiven the potential for cross-border displacement to increase the vulnerability of refugees to inferior outcomes, it was reassuring that a high proportion of refugees were virologically suppressed in the present study. In multivariable analyses, no independent association was found between refugee status and unsuppressed viral load after adjusting for age, sex, time on HAART, time from diagnosis to HAART start, temporary migration in the past year and time to clinic. Consistent with evidence from a Canadian setting showing an adverse impact of temporary migration , travel p = 0.05) and in proportions with children . Non-disclosure of HIV status has previously been shown to affect adherence [The finding that women were more likely to have achieved viral suppression could have been due to gender differences in proportions disclosing their status to partners . Moreover, there are differences between refugee settings  in relation to service-provision challenges . SocioecFactors identified from these data will help to locate those who might benefit from targeted interventions. To this end, additional counselling for men on HAART, support for those HAART clients who spend lengthy periods in transit to access treatment and care, and those who do not consistently refill their HAART prescriptions as monitored by the pharmacy, could prove to be beneficial. Risk assessments for clients who may travel for extended periods could be implemented to ensure that consistent medication supply is available and contingency plans are in place. Use of mobile phones, either through training in using personal alarms, or more actively through a text-message intervention, may help to address some of these challenges , 37. GivThis study had important limitations. Selection bias in the host community group may have affected our findings as response rates were high in both groups, but slightly lower in the host community. Moreover, the recruited host community sample represented 6 % of the target population. As non-participants may have possessed characteristics leading to bias, we compared routine socio-demographic indicators of the study sample with a simple random sample of 150 host community clients drawn from the clinic database. The random sample was statistically similar to the study sample on all socio-demographic indicators with the exception that ethnic Chinese clients were over-represented in the study sample. This could have introduced bias as ethnic Chinese Malaysians tend to have higher household incomes than other ethnic groups in Malaysia . Given tThis study excluded asylum-seekers who began HAART in their country of origin and who may have been vulnerable to inferior outcomes given the possibility that their HAART was exhausted prior to gaining refugee status and becoming eligible for the national treatment program. These cases were routinely expedited and programs should continue to facilitate and improve pathways to treatment for asylum-seekers. Strengths of the study included detailed adherence assessment using self-report and pharmacy claim measures in accordance with best-practices , collectIn summary, the high proportion of refugee and host community clients attending this public sector clinic who achieved viral suppression supports the notion that providing HAART to these groups on an equitable basis in this urban setting is both feasible and beneficial. Given the current global reduction of funding for HIV, the future sustainability of HAART for refugees needs to be critically assessed. The Malaysian national program fully subsidises first-line treatments for refugees; however, second-line treatments and virological monitoring are paid for by UNHCR. The concern is that national treatment programs that currently include refugees may opt to exclude them in the future if funding continues to decline. If the goal of universal access to treatment is to be reached and the public health benefits of antiretroviral therapy are to be realised, refugees and other conflict-affected persons must be fully included in country and regional proposals and planning for HIV and AIDS.Supplementary material 1 (DOCX 15 kb)Below is the link to the electronic supplementary material.


Background: As antiretroviral treatment (ART) programmes in resource-limited settings mature, more patients are experiencing virological failure. Without resistance testing, deciding who should switch to second-line ART can be difficult. The consequences for second-line outcomes are unclear. In a workplace- and community-based multi-site programme, with 6-monthly virological monitoring, we describe outcomes and predictors of viral suppression on second-line, protease inhibitor-based ART.Methods: We used prospectively collected clinic data from patients commencing first-line ART between 1/1/03 and 31/12/08 to construct a study cohort of patients switched to second-line ART in the presence of a viral load (VL) ≥400 copies/ml. Predictors of VL<400 copies/ml within 15 months of switch were assessed using modified Poisson regression to estimate risk ratios.Results: 205 workplace patients  and 212 community patients  switched regimens. At switch compared to community patients, workplace patients had a longer duration of viraemia, higher VL, lower CD4 count, and higher reported non-adherence on first-line ART. Non-adherence was the reported reason for switching in a higher proportion of workplace patients. Following switch, 48.3% (workplace) and 72.0% (community) achieved VL<400, with non-adherence (17.9% vs. 1.4%) and virological rebound (35.6% vs. 13.2% with available measures) reported more commonly in the workplace programme. In adjusted analysis of the workplace programme, lower switch VL and younger age were associated with VL<400. In the community programme, shorter duration of viraemia, higher CD4 count and transfers into programme on ART were associated with VL<400.Conclusion: High levels of viral suppression on second-line ART can be, but are not always, achieved in multi-site treatment programmes with both individual- and programme-level factors influencing outcomes. Strategies to support both healthcare workers and patients during this switch period need to be evaluated; sub-optimal adherence, particularly in the workplace programme must be addressed. As antiretroviral treatment (ART) programmes in resource-limited settings mature, patients are increasingly experiencing first-line, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based, treatment failure necessitating a switch to second-line, protease inhibitor (PI)-based regimens The consequences of remaining on a virologically-failing first-line regimen include immunological and clinical progression and, with increasing duration of viraemia, accumulation of resistance This study aimed to describe second-line ART outcomes in a large workplace- and community-based multi-site programme, where, in line with South African national guidelines, 6-monthly viral load (VL) monitoring is standard of care. In addition we assessed whether co-variates available at the time of switch predict early viral suppression on second-line ART.This observational retrospective cohort analysis used prospectively-collected routine clinical data from the ART programmes of Aurum Institute, South Africa. These programmes, located within five provinces of South Africa , comprise a workplace programme, with 56 clinics serving employees of predominantly mining companies; and a community programme, with 81 urban and peri-urban private general practitioner and non-government organization clinics serving patients with limited resources 3, or CD4≤350 cells/mm3plus WHO stage III. In the community programme, criteria for first-line ART  were WHO stage IV or CD4≤200 cells/mm3. Similar criteria for switching to second-line ART were used in both programmes. Interventions to improve adherence were instigated following the first detectable VL, and VL was repeated 3-6 months later. A switch to second-line ART was recommended in patients with two raised VLs >1000-5000 in the presence of good adherence. Second-line ART comprised AZT, didanosine (ddI) and boosted lopinavir (bLPV); or abacavir (ABC), ddI, bLPV in the community and workplace programmes, respectively. Patients collected ART at 1-3 monthly intervals. All HIV-related treatment was free of charge.In the workplace, patients were eligible for ART  if WHO stage IV, CD4≤250 cells/mmCD4 count and VL were monitored at baseline, 6 weeks and 6 monthly intervals after commencing or switching ART. All community clinics were doctor-led; however some workplace clinics were nurse-led with doctors consulted for management of virological failure. Patients were offered adherence counseling at each attendance, with intensified counseling for those with suboptimal adherence.Patients were eligible for inclusion in the study if they (1) switched from first- to second-line ART between 1/1/2003 and 31/12/2008; (2) ≥15 years old at switch; and (3) VL >400 copies/ml at switch . Data up to 31/3/2010 were included, allowing all patients 15 months potential follow-up.At each visit, healthcare workers recorded data on symptoms, self-reported adherence, adverse events, prescriptions and reason for stopping or changing medication on standardized data collection forms. Before commencing ART, data were collected on patient’s self-reported previous exposure to ART. Reasons for leaving the programme, derived from patient or relative self-report, and active follow-up of patients missing appointments, were recorded on deregistration forms. Data capturers entered all forms into a central database with laboratory data transferred electronically from the central laboratory. Where civil identification numbers were available, deaths were identified through the National death register; and in the workplace, through employment records and hospital death registers. Where data were missing, clinic files were reviewed using a standardised data collection form. All community sites used a central off-site pharmacy. These dispensing records were used to confirm regimens and dates dispensed.viral suppression on second-line ART, which was defined as ever having achieved a VL<400 copies/ml between 2 weeks to 15 months of switching regimens. Secondary outcomes were defined as (1) alive and in care: no record of deregistration or loss to follow-up (no clinic contact for ≥6 months) by 15 months; (2) change in CD4 count: CD4 at 12 months (+/−3 months) minus CD4 count at switch (6 months before to 2 weeks after switch); (3) reported non-adherence: patient report of missing any second-line ART based on 7 day recall and/or healthcare worker recorded treatment interruption for non-adherence within 15 months of switch.The primary outcome was Exposures on first-line ART , exposures at time of switch  and demographic data  were considered as potential predictors of early virological suppression on second-line ART. An association between adherence on second-line ART and viral suppression on second-line ART was explored, however this variable was not included in our multivariable analysis as it was considered to lie on the causal pathway between our exposures of interest and the primary outcome.Non-adherence on first-line ART was defined as patient report of missing any first-line ART based on 7 day recall and/or healthcare worker recorded treatment interruption for non-adherence at any time-point on first-line ART. Duration of viraemia was defined as the time period between the first VL >400 copies/ml following viral suppression to date of switch, where all interim VLs were >400 copies/ml. For patients with more than one episode of viraemia and re-suppression on first-line ART, only the viraemic period immediately preceding switch was considered. The variable was categorised as<12 months and ≥12 months. Not all patients were known to have achieved viral suppression on first-line ART therefore the following assumptions were made: (1) ART-naive patients with no evidence of viral suppression on first-line ART were considered viraemic since initiating ART; (2) patients who were transferred in with no subsequent viral suppression on first-line ART were categorised as viraemic for ≥12months.reason for switch was defined as treatment failure, non-adherence or other e.g. toxicity. If, both non-adherence and treatment failure were documented, the primary reason for switch was defined as non-adherence; if treatment failure and other reasons were documented the primary reasons was defined as treatment failure.Healthcare workers could document more than one reason for stopping the NNRTI-regimen. For the purposes of the analysis the primary Modified Poisson regression with robust standard variance was used to estimate the association of exposures with viral suppression using the risk ratio vs. workplace) was an effect modifier for multiple covariates  therefore analyses are presented stratified by programme. Sensitivity analyses were performed by restricting analyses to patients who were ART-naive on initiating ART within the programme. Analyses were undertaken using STATA v11 .Programme  had a documented VL ≥400 copies/ml at switch and were eligible for inclusion in the study .vs. community programme. In both programmes, of the 62 patients classified as non-adherent on first-line ART, 21% of patients self-reported non-adherence and 84% had ART modified or interrupted for non-adherence by healthcare workers. More patients in the workplace programme were prescribed a second-line regimen consistent with programme guidelines (90.7% vs. 59.0% in the community programme); however 87.7% of community patients did modify at least one of the NRTI backbone drugs in addition to receiving a bPI.The characteristics of patients who switched to second-line ART are presented in vs. community programme; 365 days (IQR 173-538) vs. 218 days (IQR 115-394) in patients with viral suppression on first-line ART. In both programmes there was a median of 3 detectable VLs prior to switch . At switch, compared to the community, patients in the workplace programme had a higher median log10 VL (4.6 [IQR 4.1-5.1] vs. 4.3 [IQR 3.7-4.6]) and a lower median CD4 count (169 cells/mm3 [IQR 97–235] vs. 187 [IQR 95–270]).A longer median duration of viraemia was observed amongst patients in the workplace vs. community 83.8% [161/192]). Non-adherence was recorded as a reason for switch in 7.8% (n = 14) of the workplace vs. 0.5% (n = 1) of the community programme. 10.6% [19/180] of patients in the workplace vs. 16.1% [31/192] in the community had other reported reasons for switching e.g. toxicity, although all were viraemic at the time of switching.In both programmes treatment failure was the commonest documented reason for switching regimens (workplace 82.2% [148/180 patients with recorded reason] The two VLs prior to switch were ≥1000 copies/ml in 80.6% (336/417) of patients switched to second-line ART; in 16.1% (n = 67) the VL at switch was ≥1000 copies/ml with the preceding measurement 400-999 copies/ml or missing; and in 3.3% (n = 14) the switch VL was 400-999 copies/ml with the preceding measurement ≥400 copies/ml or missing.vs. 72.0% (N = 152), respectively, having achieved viral suppression (p<0.01) by 15 months. Patients in both programmes had a median of 5 VLs following switch, with 87.3% (workplace) and 88.7% (community) with ≥1 measurement. Of the 250 patients who achieved viral suppression, 19.2% had no further VL measurements within the follow-up period. Of those with further measurements, 35.6% (26/73) of patients in the workplace vs. 13.2% (17/129) of those in the community experienced a subsequent episode of viral rebound to ≥400 copies/ml . At 12 months (+/−3 months), of the patients who were still in care, 46.8% (59/126) of workplace and 72.0% (116/161) of community programme had a VL<400 copies/ml.Outcomes stratified by programme are presented in vs. 1.4% [community]). In both programmes, of the 40 patients classified as non-adherent on second-line ART, 19% were identified through patient self-report and 83% through healthcare workers modification or interruption of ART for non-adherence.Patients in the workplace had a lower mean CD4 count increase at 12 months of second-line ART than those in the community programme (p<0.01). Non-adherence was reported in a higher proportion of patients in the workplace, compared to the community programme (17.9% [workplace] 10 VL (adjusted risk ratio [aRR] 1.59 [95% CI: 1.09-2.34] for<4 vs. ≥5) and younger age (aRR 0.87 [95% CI: 0.79-0.95]/5 year increase) at switch were the strongest predictors of viral suppression. In addition, our data suggests an association between switch for non-adherence vs. treatment failure (aRR 0.45 [95% CI: 0.17-1.16]) and lack of viral suppression on second-line ART. While the association did not reach statistical significance, the effect size was large. Duration of viraemia was not associated with viral suppression on second-line ART.Unadjusted and adjusted analysis of variables associated with viral suppression in the workplace and community programme are summarised in vs. ≥12 months). Patients who were transferred into the programme on ART, and those switched at a higher CD4 count were more likely to suppress following switch. Sensitivity analyses of both programmes, restricting to ART-naïve patients, resulted in similar models (data not presented).In adjusted analysis of the community programme, shorter duration, but not magnitude of viraemia, predicted viral suppression  with these patients requiring a longer period to address adherence issues before the regimen is switched. However, patients considered adherent are switched quickly; this is consistent with these individuals being more likely to achieve viral suppression.In the workplace programme, switch VL<10000 was one of the strongest predictors of viral suppression. While patients switched at higher VLs may take longer to suppress, the great majority should have achieved viral suppression by 15 months. An alternative explanation is that a high VL reflects non-adherence Not only were patients in the workplace programme less likely to achieve viral suppression on second-line ART, they were also more likely to be lost to the programme and to experience viral rebound following initial suppression. On univariable analysis of data from the workplace programme non-adherence on second-line ART was associated with failure to achieve viral suppression. In the community programme the analysis was underpowered to assess an association due to low levels of reported non-adherence. While it is possible that failure to achieve viral suppression and viral rebound is due to emergence of early PI resistance we feel this is unlikely; other studies in resource-limited settings indicate that early second-line failure is more likely to be due to non-adherence, with PI mutations rarely seen and low PI concentrations reported Although predictors of viral suppression differed between programmes, overall the findings are consistent with other studies; duration and magnitude of viraemia et al. report differences in switching rates between urban and rural sites, while others have found clinic type to be associated with second-line virological failure Other studies in this setting have also highlighted differences in switching rates and first- and second-line outcomes by site The observed differences in programme outcomes may in part be due to the different patient populations, both in terms of individuals and the community, and the healthcare systems. The workplace population was older, predominantly male, comprised largely of migrants living in close proximity to their site of work, with access to only one major healthcare provider. In contrast patients accessing the community programme were younger, mostly female, and while potentially migrants, had a choice of healthcare provider.vs. a government public clinic et al. report similar findings; patients switched after only one VL, who were considered to be transfers into care on ART, were more likely to achieve viral suppression on second-line ART Higher levels of non-adherence were reported amongst patients on first- and second-line ART in the workplace, compared to the community programme. While differences in non-adherence between programmes may be due to differences in reporting, studies conducted in this workplace setting have demonstrated multiple barriers to maintaining adherence including lack of social support, uncertainty about ART’s health benefits, belief in traditional medicine and patient-provider language barriers This study included large patient numbers across multiple sites. Extensive efforts were made to limit measurement bias and reduce effects of missing data by reviewing clinic notes, verification of switch date by cross-checking with pharmacy data, and ascertainment of deaths through multiple sources .There are limitations to our analysis. It was based on routinely collected programme data; clinic- and contextual level covariates e.g. clinic staffing levels or patients’ migrant status which could influence outcomes were not available. Due to lack of resistance data, incomplete programme reporting of non-adherence and inaccuracy of self-report as a measure of adherence, we were unable to fully explore the respective roles of resistance and adherence in early second-line virological outcomes. In addition, as programme acted as an effect modifier for multiple covariates, our analysis was stratified by programme. We were therefore unable to quantify the effect of programme (workplace vs. community) adjusted for potential confounders. Other limitations include that, for pragmatic purposes, our definition of duration of viraemia was a composite measure; for patients who did not achieve viral suppression on first-line ART, duration of viraemia was dependant on knowledge of pre-programme ART exposure and duration in programme. While our definition was subject to measurement error we do not believe it has resulted in bias; there was no evidence of co-linearity between ART exposure and duration of viraemia in the community programme multivariable model, and using an alternative definition based on duration of observed viraemia while in programme, similar associations were found. Also, with no difference in frequency of virological monitoring between programmes it is unlikely that detection bias would explain the differences in duration of viraemia, nor indeed virological outcomes. Finally in both second-line cohorts, the majority of patients were cared for by four clinics and the results may therefore be biased towards practices in these larger clinics. It is possible that the programmatic differences we have described in this study relate more to the individual clinics, rather than the programmes themselves. In a larger study looking at predictors of switching to second-line ART we found switching varied markedly by clinic. Programme, however was not associated with switching, nor did it account for clinic-level clustering The results from this study reflect the real-life dilemmas encountered in managing virological failure and switching to second-line ART in a resource-constrained setting. We demonstrate that it is possible to achieve high levels of viral suppression on second-line ART in multi-site programmes; however this is not true of all settings with both individual- and programme-level factors influencing outcomes. Despite similar guidelines, switching practices differed between programmes. With no access to resistance tests and imperfect adherence assessment tools, deciding who is failing therapy and might benefit from switching is difficult. The factors driving sub-optimal adherence, particularly in the workplace programme, need addressed and strategies to support switch decisions, such as targeted resistance tests, which may be cost-neutral, warrant further investigation


We investigated whether there are differences in the effects on microbial translocation (MT) and enterocyte damage by different antiretroviral therapy (ART) regimens after 1.5 years and whether antibiotic use has impact on MT. In a randomized clinical trial (NCT01445223) on first line ART, patients started either lopinavir/r (LPV/r) (n = 34) or efavirenz (EFV) containing ART (n = 37). Lipopolysaccharide (LPS), sCD14, anti-flagellin antibodies and intestinal fatty acid binding protein (I-FABP) levels were determined in plasma at baseline (BL) and week 72 (w72).The levels of LPS and sCD14 were reduced from BL to w72 . The levels of anti-flagellin antibodies had decreased at w72 , although significantly only in the LPV/r arm. I-FABP levels increased at w72 , although significantly in EFV treated patients only. Patients given antibiotics at BL had lower sCD14 levels at w72 as revealed by ANCOVA compared to those who did not receive .Markers of MT and enterocyte damage are elevated in untreated HIV-1 infected patients. Long-term ART reduces the levels, except for I-FABP which role as a marker of MT is questionable in ART-experienced patients. Why the enterocyte damage seems to persist remains to be established. Also antibiotic usage may influence the kinetics of the markers of MT.NCT01445223ClinicalTrials.gov  A sustained control of the human immunodeficiency virus type 1 (HIV-1) replication is obtained by antiretroviral therapy (ART) in the majority of patients, reducing plasma HIV-1 load to undetectable levels. However, HIV-1 persists in reservoirs like latently infected CD4+ T cells Several markers are used to assess microbial translocation (MT) in patients with HIV or inflammatory bowel disease The origin of low-level viremia in patients on suppressive ART has been disputed. Residual virus replication from anatomical compartments like the gut could be one of the explanations. Firstly, levels of HIV-1 DNA and RNA were substantially elevated in the gut compared with peripheral blood in patients on ART with <40 HIV-1 RNA copies/ml, indicating that the gut may serve as a potential source of viremia during suppressive ART In the present study, we analyzed the levels of LPS, sCD14, I-FABP, and anti-flagellin antibodies, at baseline (BL) and after 72 weeks (w72) of ART in a controlled randomized clinical trial in which the patients received either lopinavir/r +2 nucleoside analogues (NRTI) or efavirenz +2 NRTI. Additionally, we studied if ongoing antibiotics treatment had an impact on the explored parameters.During 2004–2007, 239 HIV-1 infected subjects received allocated intervention after written consent in a Scandinavian randomized clinical phase IV efficacy trial (RCT) . The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Pneumocystis jiroveci prophylaxis (PCP) (n = 24) or for treatment of pneumonia (n = 2), or clindamycin (n = 1). Also, two were on Mycobacterium tuberculosis treatment, and one was on fluconazole. At w72, TMP-SMX was given as PCP prophylaxis (n = 9), and one patient received nitrofurantoin; 8 of these 10 had had TMP-SMX at baseline.Data on antibiotic therapy was available in 63 patients of whom 29 were given antibiotics at baseline (BL) (n = 27) and/or week72 (w72) (n = 10), while 34 had not received antibiotics at any of the two time points . At BL, + T-cell counts were measured as part of the clinical routine with Cobas Amplicor , and flow cytometry, respectively.HIV RNA load and CD4Plasma samples obtained at the sampling day were frozen at −80°C and later thawed. The analyses were performed blindly in relation to clinical data and treatment outcome. Levels of LPS were measured by limulus amebocyte assay  as previously described S. typhimurium . It is known that human sera have a similar recognition pattern of flagellin monomers whether isolated from flagellated E. coli or S. typhimuriumS. typhimurium (25 ng/well). The following day, plasma samples from HIV-1 patients were diluted 1∶1000 and applied to the MWP. After incubation and washing, the MWPs were incubated with HRP-conjugated anti-human IgG. For total IgG ELISA, the manufacturer’s procedure was followed .Antibody titers to flagellin, and total IgG levels were assessed by an in-house anti-flagellin specific IgG ELISA Data were analyzed using GraphPad Prism v. 5.02 and R 2.13.1. Independent groups were compared using Mann-Whitney U-test and paired data analyzed with Wilcoxon signed rank test. Correlations were analyzed by Spearmańs rank test. Differences in LPS, sCD14, I-FABP and anti-flagellin IgG levels between patients with or without antibiotics were analyzed with ANCOVA using covariates age, sex, log viral load and CD4+ T-cell count at BL or w72, and residual plots were inspected. Model selection was done by backward elimination with removal of variables if P>0.1.Following initiation of ART, all patients achieved plasma HIV-RNA <50 copies/mL within 24 weeks, except for five patients . Four of these reached undetectable HIV-RNA at w72. Two patients had a relapse with detectable HIV-RNA at w72 (190 respective 640 c/mL). No statistically significant differences were found at BL or follow-up between the two arms . BL CD4+The overall plasma levels of LPS were reduced at w72 compared to BL  . The redSimilar to LPS, plasma levels of sCD14 were reduced at w72 compared to BL   in both At BL, no difference was found in plasma I-FABP levels between the treatment groups. At w72, the overall I-FABP concentrations had increased  . The eleAnti-flagellin antibodies were detected in all subjects. ART reduced the levels in the whole cohort (median OD 0.35 [IQR 0.22–0.61] at BL vs. 0.31 [IQR 0.21–0.5]) at w72; p = 0.0004) . In the As expected, the total IgG concentrations were reduced at w72  in the entire cohort, and in both treatment arms ; . The anti-flagellin IgG:total IgG ratio was reduced between BL and w72 in whole cohort  and LPV/r arm , supporting that the decrease of anti-flagellin IgG was specific. This reduction was not observed in EFV treated . LPS and anti-flagellin antibodies correlated at BL  and at w72 . On the contrary, there was no significant correlation at BL or w72 between anti-flagellin antibodies and CD4+ T-cells, VL, sCD14 or I-FABP, respectively.We explored the impact of antibiotics on markers of MT with three comparisons using ANCOVA adjusting for significant covariates. At BL, no difference was found between patients with or without antibiotics. At w72, the levels of sCD14 were lower in patients with ongoing antibiotic treatment vs. those without . Also, in the untreated group at w72 the patients who had been treated with antibiotics at baseline had lower levels than those who had been untreated at baseline . Finally, the change in the sCD14 levels between BL and w72 was calculated. A difference between antibiotic treated vs untreated patients at BL was then found  . No effeThe microbial translocation (MT) markers assessed in our study  were all increased in plasma before treatment and ART influenced the levels during the follow-up period of 72 weeks. The reliability of our results is strengthened by the fact that the patients were included in a randomized clinical trial and were followed closely before, during and after the study. Based on the randomization, we found that the effects on the selected MT parameters could partly differ depending on the type of ART and if antibiotics were given or not. We therefore suggest that other factors than HIV treatment in itself may be relevant for the kinetics of the biomarkers which should be considered when interpreting studies on MT in HIV-1 infected patients.Data from our RCT cohort showed that the plasma levels of LPS were significantly reduced after 72 weeks of ART with similar pattern in patients treated with NNRTI or PI/r containing therapy. Similar observations on the decrease of plasma LPS after ART have been reported in some The effect on sCD14 has also been disputed with studies showing decline Our untreated patients exhibited elevated plasma levels of I-FABP, as compared to historical healthy controls The bacterial flagellin is known as a microbial compound with strong immune modulatory properties that has an essential role in conditions with intestinal damage, like IBD. Hence, flagellin is regarded as a dominant immune antigen in Crohńs disease (CD) where the antibodies to bacterial flagellin (Anti-CBir1) are detected in about half of patients Antibiotic treatment leads to changes in the gut microbiota Collectively, we found that markers of MT were reduced after 72 weeks of ART. EFV and LPV/r based ART, which had similar virological outcome, presented with somewhat different effects on the kinetics of MT markers. Thus, although the profiles of the established markers LPS and sCD14 were unified after 72 weeks of treatment, the levels of I-FABP increased and anti-flagellin antibodies were not significantly reduced, respectively, in the patients on EFV containing therapy. Our data underscore the importance of unraveling the multifaceted correlations between microbial translocation, immune activation, antibiotics usage, HIV-1 replication and the chosen ART. Further longitudinal studies should address this complex issue.Checklist S1CONSORT Checklist.(DOC)Click here for additional data file.Protocol S1Trial Protocol.(DOC)Click here for additional data file.


Signature of the Comprehensive Peace Agreement (CPA) in 2005 marked the end of the 20 year war in Southern Sudan. However, the decades of war and lawlessness have completely disrupted the healthcare infrastructure in the whole of southern Sudan. HIV sero-prevalence in the western equatorial state of Southern Sudan (12.1%) is the highest in the country. the massive numbers and mobility of internally displaced persons as well as insecurity due to frequent rebel attacks make providing ART for HIV infected persons in this part of Africa very challenging.This study highlights the challenges and achievements of international medical corps, with support from the WHO, in providing HAART to returning refugees and internally displaced persons in western equatorial region of Southern Sudan.We analyzed clinic data of 159  adults were started on ART between July 2009 and march 2010. Most (69%) had been living in refugee camps while 12% were internally displaced persons at the time of ART commencement. 78% of patients presented with WHO stage 3 or 4 symptoms. All new patients went through a 3 day period of treatment preparation prior to ART commencement. Treatment education in the local language was done at group and individual levels during clinic visits. Songs addressing adherence were developed and used during Support group sessions to reinforce key adherence messages.68% of patients had baseline CD4 testing prior to commencing ART. Mean baseline CD4 count was 97cells/uL. All patients are presently on first line HAART. 65% of patients were started on AZT/3TC/NVP, 20% on AZT/3TC/EFV, and 15% on D4T/3TC/NVP. The commonest side effect observed were anaemia (6%), skin rash (4%), and gastro-intestinal discomfort (3.5%).Of the 102 patients who had taken HAART for at least 6 months, 88% reported adherence levels of >95% (had missed less than 3 doses within last month). Adherence was higher in females (92%) compared to males (80%). Of those who reported missing more than 3 doses, 71% gave rebel attacks as the reason they were unable to return to the clinic for their drug pick-ups.Despite challenges related to insecurity in Southern Sudan, successful antiretroviral therapy can be provided. Good level adherence remains an important determinant of success of ART and efforts must be made to institute comprehensive treatment education as a key strategy especially in resource limited settings.


To examine the role of antiretroviral drugs (ART), HIV-related and traditional risk factors on the incidence of chronic kidney disease (CKD) in HIV-infected patients.Prospective hospital-based cohort of HIV-infected patients from 2004 to 2012.2 at 2 consecutive measurements ≥3 months apart. Poisson regression models were used to study determinants of CKD either measured at baseline or updated. ART exposure was classified as ever or never. We additionally tested the role of tenofovir (TDF), whether or not prescribed concomitantly with a Protease Inhibitor (PI), taking into account the cumulative exposure to the drug.CKD was defined using MDRD equation as an estimated glomerular filtration rate (eGFR) less than 60 ml/mn/1.73 m2 were followed for a median of 5.8 years. At the end of follow-up, 96% had received ART, one third of them (35%) jointly received TDF and a PI. Average incidence rate of CKD was 0.95% person-years of follow-up. Incidence of CKD was higher among women (IRR = 2.2), older patients (>60 y vs <45 y: IRR = 2.5 and 45–60 y: IRR = 1.7), those with diabetes (IRR = 1.9), high blood pressure (IRR = 1.5), hyperlipidemia (IRR = 1.5), AIDS stage (IRR = 1.4), low baseline eGFR (IRR = 15.8 for 60<eGFR<70 ml/mn/1.73 m2 vs >90 and IRR = 7.1 for 70<eGFR<80 ml/mn/1.73 m2), current CD4+<200 cells/mm3 vs >500/mm3 (IRR = 2.5), and exposure to TDF (IRR = 2.0). Exposure to TDF was even strongly associated with CKD when co-administered with PIs . A higher risk of CKD was found when tenofovir exposure was >12 months [IRR = 3.0 with joint PIs vs 1.3 without (p<0.001)]. A vast majority of those developing CKD (76.6%) had a baseline eGFR between 60 and 80 ml/mn/1.73 m2.4,350 patients (74% men) with baseline eGFR>60 ml/mn/1.73 m2, a thorough control of CKD risk factors is warranted. The use of TDF, especially when co-administered with PIs, should be mentioned as a relative contraindication in presence of at least one of these risk factors.In patients with eGFR between 60 and 80 mL/min/1.73 m Nephrotoxicity of indinavir, tenofovir and more recently of boosted protease-inhibitors (PI/r) others than indinavir, have been reported In a large ongoing clinic-based cohort of HIV-infected patients, we analysed the respective role of traditional versus HIV-related risk factors of CKD and the potential interaction between exposure to TDF and boosted PIs.Written informed consent was taken from all the study participants. The study was approved by the Ethics committee of Bordeaux University Hospital (Comité de protection des personnes).The ANRS CO3 Aquitaine Cohort is a prospective hospital-based cohort of HIV-1 infected patients under routine clinical management, initiated in 1987 in the Bordeaux University Hospital and four other public hospitals in the Aquitaine region, South Western France. Inclusion criteria are: adult patients of the participating hospital wards with confirmed HIV-1 infection, having at least one follow-up after the first report, and having given informed consent. Visits occur usually every three months if the patient is treated, every six months otherwise. Detailed presentation of the cohort has been reported elsewhere As creatinine was measured using a kinetic compensated Jaffe assay traceable to an Isotopic Dilution Mass Spectrometry (IDMS) determination, and as ethnicity was not registered in our cohort, glomerular filtration rate (eGFR) was estimated by the IDMS-traceable MDRD equation without ethnicity eGFR = 175× (serum creatinine µmol/L×0.0113) −1.154×age −0.203×0.742 .CKD-Epi Equation was not used as it is validated only with enzymatic assays 2 or BMI >30 kg/m2, creatininemia <30 µmol/L, ascites) or when data were not sufficient enough to calculate MDRD formula, or if their first eGFR measure was <60 mL/min/1.73 m2 , or if they had less than two eGFR measures after a first normal measurement.Patients were included in this analysis if they had a follow-up visit between January 2004 and June 2012. Their follow-up was taken into account until December 2012. Patients were not included in this analysis if MDRD was not validated to estimate GFR  <18 kg/m2 three months apart.Our main outcome was the incidence of chronic kidney disease (CKD), defined as two eGFR measures <60 ml/min/1.73 mExplanatory variables were either fixed or updated. Fixed variables included gender, HIV transmission group (injection drug user or other), initial eGFR  and age . Updated variables included BMI, AIDS stage, delay since HIV diagnosis, having reached the AIDS stage, Hepatitis C Virus (HCV) co-infection (defined as the detection of anti-HCV antibodies at least once at baseline or during follow-up), Hepatitis B Virus (HBV) co-infection (defined as the detection of HBV antigen at least once), history or presence of diabetes , history or presence of high blood pressure (defined by the use of antihypertensive agents or systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg or diagnosis reported by physician), history or presence of hyperlipidemia , plasma HIV1-RNA (≥50 copies/mL), CD4 cell count and exposure to ART.We computed the cumulative exposure to each class of ART since enrolment in the ANRS CO3 Aquitaine Cohort including nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), and to each individual ART. We used dichotomous variables (ever vs never) to avoid biases due to the modification of drugs regimens according to the evolution of renal function assessment .Person-years accrued from inclusion in this analysis (January 2004 or after) until the earliest of chronic kidney disease, loss to follow-up (LTFU) or close of the dataset (31 December 2012). LTFU was defined as not having attended the clinic since at least 24 months while being alive and without CKD at the last visit.Incidence rate of CKD was calculated as the number of cases of CKD divided by the number of person-years of follow-up (PYFU). Cumulative probability of having CKD was estimated by the Kaplan-Meier method. Poisson regression models were used to study determinants of CKD whether measured at baseline or updated.A multivariable final model was obtained by fitting a backward selection procedure from an initial model containing all variables with a p<0.25 in the univariable analyses. Statistical significance for selection was set at 0.05.Tenofovir exposure was processed in different ways. In a first analysis, exposure to tenofovir was classified as ever/never as other ART-exposures. In order to investigate our hypothesis about increased nephrotoxicity of tenofovir when co-administrated with PI, two additional analyses were performed:firstly, tenofovir exposure was classified in four categories: never exposed, exposed less than 6 months, expose more than 6 months with joint exposure to PI during at least 6 months and ever exposed more than 6 months without joint exposure to PI during at least 6 months.secondly (and despite biases mentioned above), cumulative tenofovir exposure was classified in five categorical variables .Between January 2004 and December 2012, 5,283 patients had at least one contact reported in the ANRS CO3 Aquitaine cohort. Among them, 933 were excluded from the analysis for the following reasons: estimation of eGFR by MDRD formula was not applicable for 412 patients  <18 kg/m2 or BMI >30 kg/m2, creatinine concentration <30 µmol/L, ascites, insufficient data to use and calculate MDRD formula), 260 patients had MDRD <60 mL/min and were considered prevalent cases of CKD and 261 patients had less than two eGFR measures after the first normal one. The main characteristics which differ (p<0.05) between included and non-included patients were: male gender (74.4% in included patients vs 63.8%), diabetes (8.0% vs 3.9%), hyperlipidemia (40.2% vs 36.3%), high blood pressure (19.5% vs 10.5%), HCV co-infection (26.6% vs 21.2%) and AIDS stage (24.4% vs 19.6%).Baseline characteristics of the 4350 patients included in the analysis are shown in 2 .During a median duration of follow-up of 5.8 years (IQR 2.5–7.5–) accounting for 21983 PYFU, CKD occurred in 209 patients within a median time of 2.1 years (IQR 0.9–4.4). Incidence of CKD was 0.95 cases per 100 PYFU, 95% CI (0.83–1.09). Median annual eGFR decline in patients who progressed to CKD was 9.0 ml/mn/1.73 mSix hundred and eighty four patients (15.7%) were LTFU.One hundred and eighty seven (5.9%) patients without CKD died during follow-up and 22 (10.5%) among the 209 patients with CKD.At the end of follow-up , 96% of Factors significantly associated (p<0.05) with a higher incidence of CKD in univariable analysis are shown in 3, AIDS stage, baseline creatinine clearance <80 ml/mn and exposure to tenofovir . When introduced individually in the final model, none of individual PIs was significantly associated with higher incidence of CKD, data not shown.In the multivariable analysis , factorsIn a first additional analysis, taking into account concomitant exposure ≥6 months of PIs and tenofovir, exposure to tenofovir was associated with a higher incidence of CKD when co-administrated with PIs: IRR = 3.0 (95% CI [2.0–4.4]) vs 1.3 [0.9–2.0] without joint PIs (p<0.001), data not shown.In a second additional analysis, taking into account cumulative exposure to tenofovir, we found that tenofovir exposure >12 months was independently associated with a higher incidence of CKD when concomitant exposure to PI was noticed: IRR = 3.0 (95% CI [2.0–4.4]) vs 1.3[0.9–1.9] without joint PIs (p<0.001). When cumulative exposure to tenofovir was between 6 and 12 months, the difference between risk of CKD, whether or not PIs were concomitantly prescribed, was close to the statistical significance .Among 209 patients who developed CKD, 184 (88.0%) had a baseline eGFR between 60 and 90 ml/min/1.73 m2 and 160 (76.6%) a eGFR between 60 and 80 ml/min/1.73 m2.All patients developing CKD but four carried at least one non HIV-related risk factors of CKD , 186 (89.0%) carried at least two of them and 133 (63.6%) at least three. A distribution of these factors stratified by exposure to tenofovir is shown in In a large clinic-based cohort of HIV-infected patients, we report a two fold increase of incidence of CKD when tenofovir was administered in combination with PIs (IRR = 3.1 vs 1.3 in the absence of PIs).2 which is of clinical significance We report an incidence rate of CKD (0.95% PYFU) very close to those already reported in other cohorts; i.e 1.12% PYFU in the John Hopkins HIV Clinical Cohort (using MDRD equation) and 1.05% PYFU in the EuroSIDA Cohort (using Cockcroft-Gault formula) As others, we found that traditional risk factors  were associated with a higher incidence of CKD The impact of age reflects the physiological change of the glomerular filtration rate when ageing. With improvement of life expectancy in ART-treated HIV patients, an increasing number of elderly patients is surviving with HIV and a high risk of CKD in patients aged over 60 years can be observed: (IRR = 2.5 when age >60 years compared to age <45 years).As expected, high blood pressure, diabetes mellitus and hyperlipidemia had a deleterious role on the onset of CKD. Therefore, these characteristics are important to consider in the daily management given their high prevalence in patients receiving ART and their modifiable nature. The potential confounding role of PIs in the associations of metabolic disorders with higher incidence of CKD was taken into account by maintaining the inclusion of the use of PIs in the final multivariate model.More constantly than in HIV-negative population, women have a higher incidence of CKD among HIV-infected individuals Specific HIV-related factor independently associated with a higher risk of CKD in our study were, as reported by other reports, history of AIDS ABCC2 gene encoding drug transporters In accordance with other cohort studies showing a deleterious impact of tenofovir on renal function Conversely to the Euro-SIDA group study cohort In few reports, where drugs were analysed individually, zidovudine, didanosine and efavirenz were associated with increased incidence of CKD Conversely to a recent report The susceptibility to renal impairment of black patients, considered as especially susceptible to HIVAN, could not be evaluated in our study as ethnicity is not registered in our database, where patients are mostly (>90%) white.As in the Euro SIDA cohort, progressing to CKD was very infrequent in our study when the estimated GFR at baseline was above 90 mL/min/1.73 m2. The vast majority of patients who developed CKD (77%) had a baseline estimated renal clearance between 60 and 80 mL/min/1.73 m2. This level of eGFR appeared to be the main contributing risk of the occurrence of CKD. This result seems to us an important message that remains somewhat under-appreciated by clinicians while it should have implications for closer monitoring and specific care management of HIV infected individuals. It seems moreover interesting to notice that we found a relatively similar incidence of CKD during each year of follow-up leading to a regular increase of the cumulative risk over time. This evolution suggests that the monitoring of the glomerular filtration rate needs to be regularly performed throughout the follow-up regardless of the level of initial measurement.Presence of proteinuria, identifying early kidney renal dysfunction, was not assessed in our study. Although no study had examined the usefulness of its systematic screening in HIV infected individuals, there is some evidence that early recognition of chronic renal impairment might be beneficial We know that the MDRD equation was developed in people with CKD, and, as such, that its major limitations are imprecision and systematic underestimation of measured GFR at higher levels In conclusion, incidence of CKD occurs frequently among treated HIV-infected patients and, with ageing of HIV-infected population, might represent an important issue in terms of mortality and incidence of cardiovascular diseases in the next future. Regular assessment of renal function and evaluation of other CKD risk factors are warranted in HIV-infected patients from the time of HIV diagnosis


We analyzed clinical progression among persons diagnosed with HIV at the time of an AIDS-defining event, and assessed the impact on outcome of timing of combined antiretroviral treatment (cART).Retrospective, European and Canadian multicohort study.. Patients were diagnosed with HIV from 1997–2004 and had clinical AIDS from 30 days before to 14 days after diagnosis. Clinical progression  was described using Kaplan-Meier analysis stratifying by type of AIDS event. Factors associated with progression were identified with multivariable Cox regression. Progression rates were compared between those starting early (<30 days after AIDS event) or deferred (30–270 days after AIDS event) cART.10 copies/mL. Clinical progression was observed in 165 (28.3%) patients. Older age, a higher VL at diagnosis, and a diagnosis of non-Hodgkin lymphoma (NHL) (vs. other AIDS events) were independently associated with disease progression. Of 366 patients with an opportunistic infection, 178 (48.6%) received early cART. There was no significant difference in clinical progression between those initiating cART early and those deferring treatment .The median (interquartile range) CD4 count and viral load (VL) at diagnosis of the 584 patients were 42  cells/µL and 5.2  logOlder patients and patients with high VL or NHL at diagnosis had a worse outcome. Our data suggest that earlier initiation of cART may be beneficial among HIV-infected patients diagnosed with clinical AIDS in our setting. In addition, as the health-care systems function differently in resource-limited settings, the results of trials conducted in these settings may not be applicable to other settings, and contradictory results may be obtained. For example, in patients with cryptococcal meningitis, early cART reduced mortality in the ACTG trial 3). As RCTs of the timing of cART in patients with OIs are likely to be infeasible in developed countries because of the low incidence of OIs, observational data from different clinical settings in Western countries may provide insight as to whether it is possible to extrapolate the information obtained from RCTs conducted in resource-limited countries and may help physicians to improve the clinical management of advanced patients.The ACTG A5164 trial versus deferred) in these individuals in eight cohorts from Europe and Canada.The aims of this study were to analyze clinical progression and survival among persons diagnosed with HIV infection at the time of an AIDS-defining event and to assess the outcome of timing of cART , Italy; INMI Spallanzani, Rome, Italy; Infectious Diseases Service, Hospital Clinic – IDIBAPS, University of Barcelona, Barcelona, Spain; the Ian Charleson Centre, Royal Free Hospital, London, UK; Southern Alberta Clinic, Calgary, Canada. This study was approved by Institutional Review Boards (IRBs) of all the above listed hospitals and IRBs specifically approved the use of data without the informed consent of the subjects, since data were analyzed retrospectively and anonymously.Eligible patients from each cohort were those who had an AIDS diagnosis (defined using the Centers for Disease Control and Prevention (CDC) criteria) from 30 days before until 14 days after their first positive HIV test. All AIDS-defining events occurring during this period were considered to be events that occurred at the time of diagnosis; any AIDS-defining event that occurred more than 14 days after HIV diagnosis was considered to be a subsequent event. Datasets were requested in a common format and included demographic data , clinical events , laboratory measurements at diagnosis and during follow-up , and information on antiretroviral use .a priori and based on our clinical experience as well as on results of several randomized clinical trials  or death, whichever occurred first. Follow-up on patients who remained alive and without a new AIDS event at the end of the study period was right-censored on the date of the patient's last CD4 count or HIV viral load, whichever was latest. Kaplan-Meier plots were used to describe progression rates among all patients after stratifying by the type of AIDS event that was present (see previous section). Factors associated with clinical progression were identified using univariable and multivariable Cox proportional hazards regression models. Factors were considered to be statistically significant if p<0.05.Clinical progression rates were compared in the early and deferred cART groups using a similar approach. These analyses were restricted to the 366 patients presenting with an opportunistic infection who could be classified into one of these two groups. Follow-up for these analyses again started at the time of HIV diagnosis, with adjustment for sex, risk group, age, CD4 count and viral load at diagnosis. Analyses were repeated considering progression to death alone, and among the subgroups of patients presenting with PCP and TB.A total of 584 patients were included in these analyses. 2 increment: 1.32 , p = 0.002). The poorer prognosis among those with NHL remained after adjustment for age and viral load ; this association remained  after adjusting for the patient's age and viral load at the time of diagnosis.Of the 584 patients, 159 were not included in these analyses because they did not have sufficient follow-up or data . An additional seven patients died within the first 30 days, leaving 418 patients who met the criteria previously defined. Overall, those who were excluded were more likely to be from the injecting drug users group (21% of those excluded vs. 10% of those included) or ‘Other’ (40% vs. 32%) risk groups and were correspondingly less likely to be from the homosexual (10% vs. 24%) risk group (p = 0.0001). Excluded patients were more likely to come from Spain (50% vs. 22%) and less likely to come from the other participating countries (p = 0.0001). Finally, largely as a result of the differences in risk groups, those excluded were more likely to be female . Baseline age, CD4 T- cells count and plasma HIV RNA levels did not differ significantly between excluded and included patients.Of the 418 patients, 366 had presented with an opportunistic infection and were included in the analysis: 178 (48.6%) received early treatment and 185 (50.5%) received deferred treatment Table 3.In unadjusted analysis, patients who deferred treatment were 32% more likely to progress to a new AIDS event or die than those initiating treatment early, although this finding was not statistically significant ; this effect was unchanged  after controlling for other clinical and demographic characteristics at baseline . Analyses of progression to death alone reached similar conclusions  although as patients who died in the first 30 days after diagnosis (n = 7) were excluded from these analyses, these findings should be interpreted cautiously.In the subgroup of patients presenting with PCP only  early treatment), 31 (20.4%) patients experienced clinical progression. As before, patients who deferred treatment were more likely to experience clinical progression, although differences were not significant, either before or after adjustment for potential confounders . In the subgroup of patients presenting with TB only  early treatment), 27 (26.0%) patients experienced clinical progression. Again, patients who deferred treatment were more likely to experience clinical progression, with differences reaching statistical significance after adjustment for potential confounders . On the other hand, 47 patients had more than one AIDS-defining opportunistic infection at the time of diagnosis . There were no association between having multiple events and clinical progression .Finally, there was no evidence that clinical progression changed over time  and there was no evidence of any interaction between the treatment effect and the calendar year (p = 0.87).A considerable proportion of patients continue to present with a CDC category C event at diagnosis of HIV infection either in developed or in developing countries. As the optimal timing for starting cART in this clinical setting has not been well-established, several recent clinical trials 3 earlier cART initiation was associated with a reduction in the risk of IRIS without compromising AIDS-free survival. As yet unpublished data from the CAMELIA 3), early cART (within 2 weeks) significantly reduced the risk of disease progression and death. In our study, the median (IQR) CD4 T cell count for patients co-infected with TB was 81 cells/µL (25–177). In this sub-group, starting cART 30 days after diagnosis carried a significantly higher probability of disease progression or death compared with patients starting cART earlier . One of the limitations of our study was that we did not know whether the patients presented pulmonary or extra-pulmonary forms of TB. Based on data from the Euro HIV/TB study TB is the second most common OI in some European settings and the most common one worldwide. The RCTs on timing of cART in the context of HIV-TB co-infection have been conducted in research-poor settings vs. 54% in patients who deferred cART for 4 weeks, P< 0.006). In a randomized trial performed in Vietnam In this way, the clinical scenario is more complex in central nervous system opportunistic infections where early initiation of cART does not always reduce mortality. One randomized trial in Zimbabwe Our study shows a trend towards a better outcome for patients presenting with an AIDS-defining condition at diagnosis of HIV infection who started cART in the first 30 days from diagnosis. For OIs other than PCP and TB, a trend towards a better outcome in patients starting cART in the first 30 days was also observed, although specific conclusions can't be reached because of limited sample size and because of the heterogeneity of conditions  that were seen in this group.Timing of cART has been shown to differ by country  and by type of AIDS-defining event . cART regimens also were broadly similar in the early and the deferred arms, with some differences depending on type of OI. In our study, the factors independently associated with disease progression and death were a diagnosis of NHL, older age, and a higher viral load at diagnosis. Prognosis was independent of CD4 count stratum, most likely reflecting the universally low CD4 counts in these patients. Of note, where clinical events occurred, they were generally observed in the first 48 weeks of follow-up, suggesting that patients who do not experience clinical progression during this period are likely to have a good subsequent prognosis. Survival analysis showed that patients diagnosed with NHL had the worst prognosis.Our study has some limitations by the fact that it is a retrospective cohort study and the information at the time of AIDS diagnosis (particularly CD4 count and VL) may sometimes be missing. Despite the large sample size, the number of patients with some AIDS-defining cancers (e.g. KS and NHL) remains low, limiting any conclusions that can be drawn relating to the timing of cART in patients with cancer. As a result, we were unable to perform sub-analyses of OIs other than PCP and tuberculosis. Furthermore, as information was not available on the location of tuberculosis, we were unable to consider tuberculosis meningitis as a specific condition. As this is an observational study, we cannot rule out the possibility of unmeasured confounders ; it is possible that any differences seen between those in the early and deferred cART groups may reflect other unmeasured differences between these patients. Of note, the seven patients who died rapidly were excluded from our analyses; thus, our conclusions are applicable only to those who survive for at least 30 days after HIV diagnosis. Finally, cause of death and reasons for never starting cART remain unknown in some patients.In conclusion, the results of our cohort study are consistent with data emerging from randomized clinical trials