Mycobacterium tuberculosis bacteremia among participants undergoing baseline mycobacterial blood culture in the ACTG A5221 STRIDE study, a randomized clinical trial comparing earlier with later ART among HIV-infected patients suspected of having tuberculosis with CD4-positive T-lymphocyte counts (CD4 counts) <250 cells/mm3. We conducted a secondary analysis comparing participants with respect to presence or absence of M. tuberculosis bacteremia.We evaluated predictors and outcomes of M. tuberculosis bacteremia. Baseline predictors of M. tuberculosis bacteremia were identified and participant outcomes were compared by mycobacteremia status.Participants with a baseline mycobacterial blood culture were compared with respect to the presence or absence of 3, HIV-1 RNA level was 5.39 (4.96–5.83) log10 copies/mL, and 18 (20.0%) had blood cultures positive for M. tuberculosis. In multivariable analysis, lower CD4 count , hemoglobin ≤8.5 g/dL , and confirmed tuberculosis  were associated with M. tuberculosis bacteremia. There were no significant differences in survival and AIDS-free survival, occurrence of tuberculosis immune reconstitution inflammatory syndrome (IRIS), or treatment interruption or discontinuation by M. tuberculosis bacteremia status. IRIS did not differ significantly between groups despite trends toward more virologic suppression and greater CD4 count increases at week 48 in the bacteremic group.Of 90 participants with baseline mycobacterial blood cultures, 29 (32.2%) were female, the median (IQR) age was 37 (31–45) years, CD4 count was 81 (33–131) cells/mmM. tuberculosis bacteremia and the increased risk of IRIS was detected.Among HIV-infected tuberculosis suspects, lower CD4 count, hemoglobin ≤8.5 g/dL, and the presence of microbiologically confirmed pulmonary tuberculosis were associated with increased adjusted odds of mycobacteremia. No evidence of an association between NCT00108862.ClinicalTrials.gov:  Mycobacterium tuberculosis from blood or bone marrow, liver biopsy, or from specimens from ≥2 noncontiguous organs [Disseminated tuberculosis is strictly defined as isolation of s organs . Dissemis organs , non-spes organs -7. Howevs organs ,9.M. tuberculosis bacteremia and to assess the effect of M. tuberculosis bacteremia on ART treatment outcomes and toxicities, we conducted a planned analysis of patients enrolled in the AIDS Clinical Trials Group (ACTG) A5221 strategy study of early versus later initiation of antiretroviral therapy for HIV-infected persons treated for tuberculosis with CD4 < 250 cells/mm3 (STRIDE), who received a mycobacterial blood culture as part of their baseline evaluation. Participants with and without bacteremic disseminated tuberculosis were compared.In order to strengthen data on clinical predictors of 3 and suspected tuberculosis. The primary endpoint was the proportion of patients who survived without a new (previously undiagnosed) acquired immunodeficiency syndrome (AIDS)-defining illness at 48 weeks. Mycobacterial blood cultures were not required by the protocol. However, all tuberculosis diagnostic information was required to be recorded by the study sites. Mycobacterial blood cultures were not standardized across sites, but were collected at the discretion of the study team prior to the administration of tuberculosis treatment and antiretroviral therapy, and were processed in laboratories adhering to Good Clinical Laboratory Practice standards. Confirmed tuberculosis was defined as detection of acid-fast bacilli in sputum smear or lymph node specimen, or a positive culture for Mycobacterium tuberculosis from sputum, lymph node, or another sterile site. Probable tuberculosis required clinician’s assessment that signs and symptoms warranted empiric tuberculosis treatment. Detailed methods and results of the study are published elsewhere [www.clinicaltrials.gov identifier NCT00108862. The quality of the data was assured by adherence to Good Clinical Practice and Good Clinical Laboratory Practice standards.A5221 was an open-label, randomized study comparing earlier ART (within 2 weeks after initiation of treatment for tuberculosis) with later ART (between 8 and 12 weeks after initiation of treatment for tuberculosis) in HIV-1 infected patients with CD4-positive T-lymphocyte counts (CD4 counts) <250 cells/mmlsewhere ,10 and aOf 806 eligible participants from 26 sites enrolled in A5221, 90 (11.2%) participants from 5 (19.2%) sites had baseline mycobacterial blood cultures and were included in this analysis.M. tuberculosis bacteremia. Covariates with p ≤ 0.10 from an exact conditional score test in univariable models were examined together in a multivariable model using the stepwise selection method. Estimated proportions of participants who survived with or without a new AIDS event at 48 weeks and failure-time plots were calculated with the use of the Kaplan–Meier method. Failure was defined at the first qualifying event. Failure times were determined as the differences between randomization and failure dates or, if censored, last clinical visit dates.Exact logistic regression models were used to investigate baseline predictors of An asymptotic normal two-sample test was employed to evaluate the difference in failure proportions. Fisher’s exact and exact Wilcoxon tests were used to assess between-group differences. Based on the sample sizes and numbers of primary endpoint, there was 12% power to detect a difference using a two-sided 0.05-level binomial test.M. tuberculosis bacteremia in a univariable exact logistic regression model.Participant characteristics at baseline, including sex; enrollment at an African site; age; CD4 count; HIV-1 RNA level; presence of an AIDS-defining illness; body mass index (BMI); hemoglobin; self-reported cough, weight loss, and fever; and confirmed tuberculosis, were evaluated as potential predictors of The protocol was approved by the following institutional review boards or ethics committees: New York University School of Medicine, NY, USA; Los Angeles Biomedical Research Institute, CA, USA; University of California San Diego, CA, USA; University of California San Francisco, CA, USA: University of Southern California, CA, USA; Lifespan Miriam Hospital, RI, USA; University of the Witwatersrand, Johannesburg, South Africa; University of KwaZulu Natal, Durban, South Africa; Asociacion Civil Impacta Salud y Educacion, Lima, Peru; Chiang Mai University Research Institute for Health Sciences and Faculty of Medicine Chiang Mai University, Chiang Mai, Thailand; National AIDS Research Institute, Pune, India; YRG Care Medical Centre, Chennai, India; National Health Science Research Committee, Lilongwe, Malawi, and University of North Carolina, NC, USA; Instituto de Pequisa Clinica Evandro Chagas, Rio de Janeiro, Brazil; Grupo Hospitalar Conceicao, Porto Alegre, Brazil; Joint Clinical Research Centre and Uganda National Council for Science and Technology, Kampala, Uganda; Kenya Medical Research Institute, Nairobi, Kenya; Moi University College of Health Sciences, Eldoret, Kenya; Health Research and Knowledge Management, Gaborone, Botswana, and Harvard School of Public Health, MA, USA; University of Zambia, Lusaka, Zambia, and University of Alabama at Birmingham, AL, USA; Comite des Droits Humains des Centres GHESKIO, Port-au-Prince, Haïti; Johns Hopkins University, MD, USA, and University of Malawi, Blantyre, Malawi; Medical Research Council of Zimbabwe, Harare, Zimbabwe; Hospital Universitario Clementino Fraga Filho, Rio de Janeiro, Brazil; Bronx-Lebanon Hospital Center, NY, USA; University of Texas Health Science Center at Houston, TX, USA; and University of Medicine and Dentistry of New Jersey Newark Campus, NJ, USA. All participants provided written informed consent.3, and HIV-1 RNA level was 5.39 (4.96–5.83) log10 copies/mL. Forty-two (46.7%) of 90 participants started early ART and 18 (20.0%) of 90 were blood culture positive for M. tuberculosis. Of those with mycobacteremia, 10 (55.6%) had positive baseline sputa for acid-fast bacilli, and 17 (94.4%) met the study definition of confirmed tuberculosis and 1 (5.6%) met the definition of probable tuberculosis at week 12.Eighty-eight (97.8%) of 90 participants with baseline mycobacterial blood cultures were from sites in Rio de Janeiro, Brazil; Lilongwe, Malawi; and Johannesburg, South Africa. Among all participants from these 3 sites, those with mycobacterial blood cultures were more often enrolled at a non-African site p < 0.001), older (p = 0.017), and more likely to report cough (p = 0.022) and weight loss (p < 0.001) compared with participants without cultures , younger age , lower CD4 count , higher HIV-1 RNA level , lower BMI , hemoglobin ≤8.5 g/dL , and confirmed tuberculosis . In the multivariable analysis, lower CD4 count , hemoglobin ≤8.5 g/dL , and confirmed tuberculosis  were associated with increased adjusted odds of M. tuberculosis bacteremia.The covariates that were significantly (p ≤ 0.10) associated with higher odds of M. tuberculosis bacteremia compared with 6 (8.3%) deaths out of 72 participants in the non-bacteremic group. The estimated difference in proportions at week 48 between the two groups was −2.5% . There were 4 (22.2%) events (1 death and 3 new AIDS-defining illnesses (1 then died) out of 18 participants in the group with M. tuberculosis bacteremia compared with 11 (15.3%) events (4 deaths and 7 new AIDS-defining illnesses (2 then died)) out of 72 participants in the group without. The estimated difference in event proportions at week 48 was −6.6% . No significant differences were observed using Fisher’s exact test in subgroup analyses . The Figure There were 2 11.1%) deaths out of 18 participants in the group with 1.1% deatM. tuberculosis bacteremia status. There were no differences by M. tuberculosis bacteremia in the occurrence of IRIS, in interruption or discontinuation of tuberculosis medications or ART due to drug toxicity, or in sputum culture conversion from positive at baseline to negative at week 8. Participants with M. tuberculosis bacteremia were significantly more likely to convert their sputum smear from positive at baseline to negative at week 8 . The higher proportion of participants with sputum conversion in the M. tuberculosis bacteremia group remained significant when missing baseline smear results were coded as positive (p = 0.036) or as negative (p = 0.007). The difference remained significant in an analysis adjusting for timing of ART initiation and CD4 count strata . There were non-significant trends in participants with M. tuberculosis bacteremia being more likely to have HIV-1 RNA levels <400 copies/mL at week 48 (p = 0.062) and experiencing CD4 count increases ≥100 cells/mm3 at week 48 (p = 0.059).Table M. tuberculosis bacteremia among HIV-infected patients suspected to have tuberculosis. We found no significant differences in survival or AIDS-free survival, occurrence of IRIS, or treatment interruption or discontinuation by M. tuberculosis bacteremia status. Occurrence of IRIS did not significantly differ between groups [M. tuberculosis bacteremia. Compared with patients without M. tuberculosis bacteremia, mycobacteremic patients were more likely to convert their sputum smear from positive at baseline to negative at week 8.We demonstrated that lower CD4 count, hemoglobin ≤8.5 g/dL, and the presence of microbiologically confirmed tuberculosis were associated with increased adjusted odds of M. tuberculosis bacteremia and we suggest that these be included in larger studies developing clinical diagnostic strategies for disseminated tuberculosis. Unlike studies of disseminated tuberculosis done among febrile patients, we did not detect an association between cough, fever, or weight loss and M. tuberculosis bacteremia. This is probably because A5221 enrolled tuberculosis suspects who would be expected to have cough, fever, or weight loss irrespective of the co-occurrence of M. tuberculosis bacteremia.Lower CD4 count, hemoglobin ≤8.5 g/dL, and the presence of microbiologically confirmed tuberculosis may assist clinicians in identifying tuberculosis suspects with M. tuberculosis bacteremia was much lower in A5221 than in other studies [The case fatality ratio of patients with  studies , and the studies , or may M. tuberculosis bacteremia was not associated with increased risk for IRIS in our analysis despite the high proportion achieving virologic suppression and CD4 count increases ≥100 cells/mm3 at week 48.The higher total body mycobacterial load assumed to be present in patients with the bacteremic disseminated form of tuberculosis combined with rapid ART-associated immune reconstitution has been suggested to increase the risk for IRIS . It is rM. tuberculosis bacteremia, mycobacteremic patients were more likely to convert their sputum smear from positive at baseline to negative at week 8. This could reflect differences in mycobacterial burden in the respiratory tract of patients with disseminated tuberculosis compared with those with primarily pulmonary disease.Compared with patients without M. tuberculosis bacteremia on patient outcomes. The use of mycobacterial blood culture during the baseline evaluation of ACTG protocol A5221 varied considerably by site and was at the discretion of the site team. This could have introduced bias. Misclassification may have occurred in the control group since not all patients without mycobacteremia were ultimately confirmed to have tuberculosis and a single mycobacterial blood culture is not 100% sensitive for the detection of mycobacteremia.This analysis had a number of limitations. A5221 was not powered to examine the effect of M. tuberculosis bacteremia. Most notably, M. tuberculosis bacteremia did not appear to be associated with increased risk for IRIS despite the high proportion achieving virologic suppression and CD4 count increases ≥100 cells/mm3 at week 48. However, larger studies with standardized and consistent use of mycobacterial blood culture are needed to confirm the findings of our analysis.Among HIV-infected tuberculosis suspects, mycobacteremia was associated with lower CD4 count, hemoglobin ≤8.5 g/dL, and the presence of microbiologically confirmed tuberculosis. Tuberculosis suspects with mycobacteremia were more likely to convert their sputum smear from positive at baseline to negative at week 8, but did not otherwise significantly differ by outcome compared to those without


Patients with human immunodeficiency virus type 1 (HIV-1) who receive antiretroviral therapy (ART) often achieve increased survival and improved quality of life. In this respect, monotherapy with darunavir/ritonavir (mDRV/r) can be a useful treatment strategy. This prospective study analyses the effect of mDRV/r on sperm quality and viral load in a group of 28 patients who had previously been given conventional ART and who had recorded a viral load <20 copies/mL for at least six months. These patients were given mDRV/r at a dose of 800/100 mg for 48 weeks. At baseline (V0), CD4, CD8, FSH, LH and testosterone levels were measured, together with HIV-1 viral load in plasma and semen. In addition, seminal fluid quality was studied before mDRV/r treatment was prescribed. At week 48 (V1), HIV-1 viral load in plasma and semen and the quality of the seminal fluid were again measured. The results obtained indicate that at V0, 10% of the patients with ART had a positive viral load in seminal fluid (>20 copies/ml), and that at V1, after mDRV/r treatment, this figure had fallen to 3%. The quality of seminal fluid was close to normal in 57% of patients at V0 and in 62% at V1. We conclude that, similar to ART, mDRV/r maintains HIV-1 viral load in most patients, and that there is no worsening in seminal fluid quality. The principal route of transmission of the human immunodeficiency virus HIV-1) is heterosexual activity. However, the risk of transmission from HIV-1 males who have successfully completed a course of antiretroviral therapy (ART) is close to zero (1:100000) if the plasma viral load has been undetectable during the previous six months, if the patient has adhered strictly to the ART and if no other sexually transmitted disease is present [ is heterSexual transmission between partners is significantly reduced when the seropositive member receives highly active antiretroviral therapy (HAART) ,3. Some Treatment guidelines for patients with HIV-1 recommend ART ,13. HoweIt has been shown that monotherapy with LPV  or with Studies have analysed monotherapy with LPV/r  and DRV/The aim of the present study was to evaluate the changes produced in the quality and viral load of seminal fluid in HIV-1 patients who had previously received ART, and who were then treated with mDRV/r for 48 weeks. Concurrently, we evaluated the viral load in seminal fluid and other parameters of semen quality in patients receiving ART, seeking to relate these parameters to CD4 lymphocytes and the CD4 nadir.HIV-1 patients were drawn from those attending the outpatient infections clinic at Virgen de las Nieves university hospital (HUVN) . These patients were receiving stable conventional ART, including two analogues of nucleotides and a third drug. All had undetectable viral load (<20 copies/mL). All these patients provided signed informed consent to participate in the study. Those with active sexually transmitted diseases at the time of sample collection were excluded. The study was approved by the hospital’s ethics committee. The patients’ data were codified to maintain anonymity, in accordance with Spanish data protection laws.Males infected with HIV-1, with undetectable plasma viral load (<20 copies/mL) for at least six months;At least 18 years of age.Patients not adhering to scheduled outpatient appointments;Patients with a history of endocrinological or genital treatment or disease that could affect semen quality.Prospective, observational study over 48 weeks, with determination at baseline (V0) and at week 48 (V1) of follow-up. All patients were informed of the nature of the study prior to the first sample acquisition. The sample was obtained by masturbation following 3–4 days of sexual abstinence.The outpatient visits were scheduled for each patient every four months. Adherence to the medication was evaluated by checking with the hospital’s pharmacy regarding the patient’s prescription record, and by questioning the patient in the outpatient clinic.The parameters recorded were age, alcohol and tobacco consumption, androgenic history, reproductive history, CD4 count, CD4 nadir, type of ART, HIV-1 viral load in plasma and seminal fluid. The parameters considered in the semen quality analysis were viscosity, visual aspect, liquefaction, volume, pH, total sperm count, percentage of sperm with progressive motility and percentage of live sperm with normal forms. The teratozoospermia index was calculated. Serology was performed for hepatitis B and C, FSH, LH and testosterone.Most of the samples were collected in the laboratory of the Reproduction Unit at HUVN. Less than 5% of the samples were collected by the participants in their own homes. In the latter case, the semen sample was maintained at body temperature and delivered to the laboratory within 45 minutes. On receipt of the sample in the laboratory, the following data were recorded: period of abstinence from sexual activity, whether any fraction of the ejaculate was lost, drugs taken, recent fever, body mass index and any recent participation in extreme sports. All samples were analysed within one hour of collection. Analyses were performed by a single, well-trained investigator with over 10 years’ experience and who regularly participates in such studies. This procedure minimised inter-individual variation in analyses and maximised the precision of the study.Each participant provided four semen samples: two before starting monotherapy and another two after 48 weeks. The interval between the first and the second of each pair of samples was 15 days.The ejaculates were analysed in accordance with WHO recommendations  and withTwo fractions were generated by centrifugation . Real time polymerase chain reaction (RT-PCR) was used to quantify RNA HIV-1 in the final sample, applying a technique adapted for HIV-1 in the COBAS analyser .Two determinations were performed on seminal fluid samples acquired 15 days apart, before commencing monotherapy. A further two were obtained following the conclusion of the monotherapy administration, separated by the same interval .t-test for related quantitative variables. The Wilcoxon test was used when the distribution was non-normal. The concentrations and total numbers of sperm, which presented a non-normal distribution (non-Gaussian), were log transformed to approximate a normal distribution [Descriptive analyses were performed on the principal variables collected. For quantitative variables, measures of central tendency (mean and median) and of dispersion (standard deviation and range) were calculated. For the qualitative variables, absolute and relative frequencies were calculated. Differences in pre and post- monotherapy values, in relation to semen quality, were evaluated using the McNemar test for the qualitative variables and the Student ribution .The level of statistical significance was set at p<0.05. IBM SPSS 19 statistical software was used throughout.Of the 31 patients who met the selection criteria and were initially selected, 28 were recruited to the study. Subsequently, three were excluded (one who refused consent and two who failed to donate semen). Of the remaining 28 patients, four did not enter the monotherapy phase (on the advice of the attending physician), although they did provide semen samples at the baseline visit. Three failed to provide a semen sample at 48 weeks, and thus 21 patients with mDRV/r finally completed the 48-week follow-up. No patient left the study due to positive viral load in plasma, or because of side effects .At baseline, 28 patients were included in the study. The mean age was 41 years (SD: 9.3), the median CD4 value was 659/mL (range: 230–1242) and the median CD4 nadir was 270/mL (range: 10–634).The ART treatment is summarised in At V0, HIV-PCR in the seminal fluid was analysed on the first sample provided by 27 patients (one was not processed because of PCR inhibition); four (15%) were positive (>20 copies/mL), with a range of 35–1210 copies/mL.The second HIV-PCR analysis in seminal fluid at V0 was performed on 22 samples from 28 patients (six were unsuccessful because of PCR inhibition); one (5%) was positive, with 399 copies/mL.At V0, 5 of the 49 samples (10%) presented HIV-1-positive viral load in seminal fluid.The data on semen quality in patients on ART (V0) are summarised in No change was observed in serostatus against hepatitis B or C, or in the hormonal profile studied .In the first seminal fluid sample, only 1 of 17 patients (6%) had a positive viral load (139 copies/mL). No results were obtained from the remaining four patients, due to PCR inhibition.With respect to the second sample, none of the 15 patients analysed had a positive viral load . Of the total sample of 32 mDRV/r patients, only one (3%) was positive. This patient was also positive at V0. The percentage of semen samples with a positive viral load was similar in monotherapy and in tri-therapy (3% vs. 10%) and no statistically significant differences were observed (p = 0.3946).With respect to semen sample quality, no statistically significant associations were observed at V0. This applied not only to CD4 levels (p = 0.781) but also to the CD4 nadir (p = 0.3). At V1, too, there were no statistically significant associations in the semen quality with respect to CD4 levels (p = 0.750) or the CD4 nadir (p = 0.595).The aim of this study was to evaluate the viral load in the genital compartment, a possible sanctuary site, following treatment with mDRV/r, and to determine whether this treatment, extended to include nucleos(t)ide analogues, improved seminal fluid quality in HIV-1-positive patients.The mDRV/r treatment combination was adopted because of its potency and ease of administration and because our team, as well as others, had considerable experience in its use .et al. [et al. [et al. [et al. [et al. [The seminal fluid viral load of the patients receiving ART was analysed in 49 samples . These samples were obtained from 27 of the 28 patients who began the study; for one patient, it was not possible to determine the viral load in any of the semen samples provided, due to PCR inhibition. Of these 49 samples, only five (10%) were positive (>20 copies/mL), with the viral load ranging from 35 to 1210 copies/mL. These values are slightly lower than those observed by Torres-Cornejo et al. . Of the  [et al.  and the  [et al. , using L [et al.  reportedOnly one patient receiving mDRV/r treatment had a positive viral load of 139 copies/mL, which cannot be compared with the viral load values of the patients receiving ART. This patient presented a positive viral load in seminal fluid while receiving ART.These findings of a very low percentage of positive viral load with mDRV/r in seminal fluid lead us to believe that this type of therapy is as safe as ART, with respect to levels of viral load seminal fluid. In the central nervous system, similarly good results have been reported for mDRV/r , 35, 36.With respect to the quality of seminal fluid, after discarding endocrinological and genital abnormalities (data not shown), only 57% of the patients receiving ART surpassed the lower limit of the WHO 2010 reference values for semen quality  see Tab. These dOf the patients who proceeded to receive mDRV/r, the percentage with normal semen rose to 62%, although the difference, as regards the overall quality of the semen, was not statistically significant . The maiAccording to our literature review, no previous studies have been conducted to compare changes in seminal fluid quality after patients proceed from ART to mDRV/r treatment, or to LPV/r in monotherapy.In our study, neither in the ART patients nor in those receiving mDRV/r were any statistically significant relationships observed between CD4 levels and seminal quality. Neither were there significant relationships between the CD4 nadir and semen quality.In view of the results obtained in the present study, we conclude that the viral load in seminal fluid has the same characteristics in ART patients as in those receiving mDRV/r, and that there was no worsening of semen quality relative to baseline. The possibility of changes in the cells and molecules of the immune system, with respect to sperm, cannot be discounted and this question needs to be analysed in future studies. The results we report could provide clinicians with guidance in providing an appropriate response to the reproductive desires of the seronegative partner of an HIV-1-positive patient . Neverth


Despite great advances in antiretroviral therapy (ART) in the last decade, several limitations remain regarding adverse effects, poor adherence, and drug-drug interactions. Switching ART in stable, virologically suppressed patients with the aim of improving tolerability and convenience is a widely used strategy in clinical practice. Several factors need to be considered when switching from a successful antiretroviral regimen, including previous virologic failure and duration of virologic suppression, genetic barriers to resistance of the new regimen and expected level of adherence. Reductions in the number of pills, drugs, or doses are the most common switching strategies.Triple therapy regimens including ritonavir-boosted protease inhibitors (PI/r) are the most frequently switched regimens. Thymidine analogues, which are now uncommon in developed countries, have been successfully replaced with non-thymidine analogues in recent years. The main aim of this switch is to prevent or improve abnormal fat redistribution.Simple one-pill triple regimens such as tenofovir/emtricitabine (TDF/FTC) plus efavirenz (EFV), rilpivirine (RPV) or Elvitegravir/Cobicistat (ELVI/Cobi) may help to improve adherence and reduce some PI/r toxicities. The use of PI/r monotherapy is accepted in EACS Guidelines for selected virologically suppressed patients and may be an option for patients with previous nucleoside analogue toxicities, such as tenofovir-related nephrotoxicity. Raltegravir may be switched to once-daily regimens to improve adherence or it may replace other drugs to avoid interactions in medically complex patients. Unboosted atazanavir is a PI-containing option for patients who do not tolerate ritonavir. Two drug regimens have been assessed in randomized clinical trials and cohort studies with different results because of negative drug interactions leading to unexpected toxicities or low efficacy in some cases.In summary, many switching options are currently available for virologically suppressed patients. However, although switching strategies may be useful for improving ART, not all regimens used in clinical practice are based on data from randomized clinical trials and not all regimens are suitable for everyone. It is therefore important to individualize treatment, taking into consideration not only patient and drug characteristics but also the best evidence available.


The long-term effects of an intensified induction regimen are unknown. In this pilot, randomized, prospective study we evaluate the effect of a short-term four-drugs induction regimen in patients with high baseline viral load.ab-initio with TDF+FTC+EFV (E) or TDF+FTC+RAL (R) were used.Naive patients with HIV-RNA>100.000 copies/ml receiving TDF+FTC+EFV+RAL (group ER) for 4 months and were then simplified to TDF+FTC+EFV. Two randomized control groups treated ion of activated CD4+CD38+HLADR+ cells (1.9% versus 3.9 and 3.8%) and CD8+CD38+HLADR+ cells (10.3% versus 16.8 and 16.5%) and a significantly better CD4/CD8 ratio .19 patients with a mean age of 38 years and mean baseline CD4 count of 334 (SD 216) cells/mcL and HIV-RNA of 5.47 log (SD 0.32) copies/mL were enrolled. No baseline significant difference was observed among groups. Early HIV-RNA reduction was significantly higher in ER compared to the other groups from week 1 to week 4 (P from 0.026 to 0.003) , thereafA four-drug regimen in naive patients with high pre-therapy viral load improves early virologic response. A quick drop of HIV-RNA seems to correlate with a sustained virologic response. Although limited in time (four months), the four-drug regimens correlates with an improved immunological response as measured by the CD4/CD8 ratio or the percentage of activated CD4+ and CD8+ cells. The reasons why this happens deserve further studies. This study highlights the importance of a personalised therapy especially in high risk patients.


Data on patients with long-term exposure to ART is scarce because controlled studies usually do not follow up patients for more than five to seven years. We were interested whether baseline parameters such as CD4 T-cell nadir or pre-treatment viraemia do have an impact on ART success after more than a decade of treatment.ELBE is a cross-sectional study on adult HIV+ patients presenting consecutively with viral suppression (<50 HIV RNA copies/mL) and with ART exposure of at least five years. In this sub-analysis, all patients with more than 10 years of ART exposure were evaluated for immune reconstitution and for intermittent transient viraemia  during the last five years.From a total of 894 patients included in the three participating ELBE centres, 524 patients had an ART exposure of at least 10 years and had been treated continuously during the last 5 years. Of these, 33.4% had at least one “blip” while 63.5% did not show any transient viraemia of more than 50 copies/mL. Patients with at least one blip had a higher pre-treatment viraemia compared to patients without blips . In patients with a pre-treatment viraemia of more than 100,000, 50,000–100,000 and less than 50,000 copies/mL, the proportions of patients with blips during the last five years were 39.5%, 30.5% and 21.8% (p=0.007), respectively. The history of an AIDS-defining illness or the CD4 T-cell nadir was not associated with a higher frequency of blips. However, CD4 T-cell nadir was a strong predictor for current CD4 T-cell counts. In patient groups with a CD4 T-cell nadir of 0–99, 100–199, 200–349, 350+ cells/µL, the median current CD4 T cells were 571, 667, 710 and 890 cells/µL, respectively. These differences remained significant when the analysis was restricted to patients with more than 15 years of ART exposure (n=268).In this large group of positively selected HIV+ patients with long-term exposure to ART of at least 10–15 years, high pre-treatment viraemia was still associated with a higher frequency of intermittent transient viraemia (“blip”). A low CD4 T-cell nadir remained associated with a lower CD4 cell recovery. The clinical implications of these findings remain to be evaluated.


Guidelines for antiretroviral treatment (cART) are published regularly, but there is little information regarding the effect of adherence to guidelines on patient outcomes. We assessed the effect of following the "when-to-start" and "what-to-start" guidelines, on treatment modifications, and on immunological and virological outcome at 12 months in a cohort of HIV-1 infected patients initiating cART from 2000 to 2010.Consecutive HIV-1 infected patients, antiretroviral naive, initiating cART from 2000 to 2010 at a University Hospital were enrolled. HIV-2 infection, cART for prevention of mother-to-child transmission or during primary HIV-infection and unlicensed drugs were excluded. The respect or not of the "when-to-start" and "what-to-start" guidelines was based on French guidelines published from 2000 to 2010. Factors associated with cART modifications at 12 months and factors associated with an HIV viral load of <50 copies/mL at 12 months were assessed by univariate and multivariate logistic regression modeling. Variations in CD4 counts from baseline were assessed by univariate and multivariate linear regression.Of 1365 patients starting cART, 151 were treated outside "when-to-start" guidelines and 150 were treated outside "what-to-start" guidelines. Not using "when-to-start" guidelines was mainly related to early initiation in young men having sex with men, and was not associated with a significantly different outcome at 12 months. Treatments that did not follow "what-to-start" guidelines were not observed in any specific population and were associated with more treatment modifications and a poorer virological outcome at 12 months.Adherence to "what-to-start" guidelines is associated with a better outcome at 12 months in HIV-infected patients initiating antiretroviral therapy. Efforts should be made to promote adherence to these guidelines. The introduction of combined antiretroviral therapy (cART) in 1996 led to a dramatic improvement in HIV disease prognosis, from a deadly disease to a manageable chronic infection compatible with a normal or near-normal life expectancy . Since tFollowing the guidelines depends on the availability of the drugs and the organization of the health-care system, but also on physicians’ personal experience. For example, prescription of not recommended drugs may occur because of the guidelines lag behind clinical trial results but also in specific clinical situations such as HCV or HBV coinfections, renal insufficiency or treatment of opportunistic infections. The availability of numerous drugs facilitates the prescription of various combinations in industrialized countries, resulting in a significant proportion of prescriptions outside the recommendations .Few studies have reported adherence to guidelines in industrialized countries -15]. So. So15]. We conducted an analysis of first line cART in a large cohort of patients who initiated cART from 2000 to 2010. We hypothesized that good adherence to guidelines would improve patients' outcome, independent of the time period. One-year outcomes were studied according to whether or not the patient's treatment followed the French national guidelines applicable during the time of treatment.The Department of Infectious and Tropical Diseases at Croix-Rousse Hospital in Lyon, France, follows approximately 2,500 HIV-infected patients yearly. The Department provides care to patients from the diagnosis of HIV infection to complications from AIDS, leading to a high retention rate. This hospital cohort is included in the French Hospital Database on HIV and follows the protocols described elsewhere . patientDemographic and biological data at baseline and at 12 months were recorded. The time from HIV diagnosis to cART initiation was also recorded, as well as the duration of the first line of treatment and the reason for treatment modification or interruption if it occurred during the first year.The timing of cART initiation ("when-to-start" guidelines) was defined as "recommended", "optional", or "not recommended" on the basis of actual CD4 count, HIV viral load, and other specific conditions such as hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection, high cardio-vascular risk, or treatment as prevention -22]. Si. Si22]. The choice of antiretrovirals and the type of combination ("what-to-start" guidelines) was defined as "preferred", "alternative", or "not recommended". Since new drugs were often classified as "alternative" before being classified as "preferred", these 2 categories were grouped for analysis. Table cART modification was defined as any change of at least 1 antiretroviral during the first year of treatment. Dosage adjustments and switch to fixed-dose combinations using the same molecules were not considered modifications.The main reason for treatment modification or interruption was classified at the time of event as virological failure (defined by a confirmed HIV-RNA >200 copies/mL at 6 months or >50 copies/mL at 12 months), toxicity/tolerance issues, simplification of treatment, patient request (including observance issues), and other reasons, including pregnancy and pharmacological interactions.U Test. The Chi2 test for linear trends was used to assess the effect of the year of guideline publication on the outcomes.Qualitative variables were reported as numbers and percentages and were compared with the Chi2 test. Quantitative variables were reported as medians with interquartile range (IQR) and were compared with the Mann-Whitney Factors associated with cART modifications at 12 months and factors associated with an HIV viral load <50 copies/mL at 12 months were assessed by univariate and multivariate logistic regression modeling. Variations in CD4 counts from baseline were assessed by univariate and multivariate linear regression.The independent variables were whether the treatments followed the "when-to-start" and "what-to-start" guidelines. The following potential confounders were tested: year guidelines were published, age at cART initiation, risk factors for HIV infection, delay between HIV diagnosis and cART initiation, presence of HBV/HCV coinfection, Centers for Disease Control and Prevention (CDC) stage, HIV viral load, and CD4 count at cART initiation.P value was≤ .15; a backward stepwise process was then implemented and models were compared with the Wald test. Baseline CD4 count was forced in the predictive model of CD4 count variation at 12 months. Baseline HIV viral load was forced in the predictive model of undetectable HIV viral load at 12 month. All statistical tests were 2-tailed, and P < .05 was considered statistically significant. The viral suppression rate at 12 months was analyzed in an intention to treat (ITT) way . The data were analyzed by Stata software 11.0 . Missing data were avoided by complete case analysis.After univariate analysis, independent variables and potential confounders were entered in multivariate models if their From January 2000 to December 2010, 1365 patients initiated cART accordingly to the inclusion criteria. The demographics and clinical characteristics of the patients at baseline are summarized in Table P < .001). Factors associated with not following the "when-to-start" guidelines at cART initiation included younger age, male gender, men having sex with men, CDC stage A-B, higher CD4 count, and lower HIV viral load at baseline.cART not following the current "when-to-start" guidelines was initiated in 151 patients (11%). Treatment not following the guidelines declined from 22% in the 2000-2001 period to 6% in 2010 (P < .001). Factors associated with initiating cART that did not follow the "what-to-start" guidelines included older age, male gender, a shorter delay between HIV diagnosis and cART initiation, CDC stage C, lower CD4 count, and higher HIV viral load at baseline. Factors associated with following or not following the guidelines are summarized in Table One hundred and thirty-two different cART combinations were prescribed; 65 that followed the "what-to-start" guidelines and 67 that were outside the guidelines. These 67 regimens outside the guidelines represented 150 patients and included suboptimal combinations such as 2 or 3 nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) (25 patients), more than 3 drugs (n = 69), 2 NRTI with a fusion inhibitor (n = 10) and other combinations of 3 drugs from 3 different classes (n = 46). cART that followed the current "what-to-start" guidelines was initiated in 1215 patients (89%) and treatments that were outside guidelines were initiated for 150 (11%). Prescription of drugs outside the current guidelines declined from 18% in the 2000-2001 period to 9% in 2010 . Similarly, the proportion of patients with CD4 counts >500/mm3 at 12 months increased from 28.6% to 43.2% (P < .001). Conversely, the proportion of patients reporting cART modification during the first year decreased from 52.1% to 22.6% (P < .001). Reasons for cART modification were virological failure in 6.6% of patients (n = 39), toxicity/tolerance issue in 41.0% (n = 244), simplification in 21.3% (n = 127), patient request in 7.9% (n = 47), and other reasons in 23.2% (n = 138).Eleven patients died during the first year of follow up. At 12 months, 64.3% of patients had an undetectable HIV-RNA <50 copies/mL, 31.9% had a CD4 count greater than 500/mmP < .001), whereas the CD4 increase from baseline was lower in these patients (P = .006).The proportion of patients with an HIV viral load <50 copies/mL at 12 months was similar for patients initiating cART with treatments that followed and did not follow the "when-to-start" guidelines, as well as the proportion of patients with a treatment modification during the first year. The median CD4 count was higher at 12 months for patients initiating cART that did not follow the "when-to-start" guidelines (P < .001), experienced undetectable HIV-RNA less frequently, and had lower CD4 counts and lower CD4 count increases at 12 months than patients initiating cART according to the guidelines (P < .001). The 12-month outcome data are summarized in Table Conversely, patients initiating cART with treatments that did not follow the "what-to-start" guidelines reported more treatment modifications (P = .004), but was not associated with treatment modification  or HIV-RNA <50 copies/mL at 12 months . Not following the "what-to-start" guidelines was associated with a higher treatment modification rate , decreased rate of HIV-RNA <50 copies/mL , and decreased CD4 count at 12 months .After univariate regression analysis, treatments not following the "when-to-start" guidelines were associated with decreased CD4 counts , and a treatment that did not follow the "what-to-start" guidelines. A sensitivity analysis was performed by excluding simplification of treatment from other causes of cART modification. This analysis gave similar results (data not shown).Factors independently associated with a greater increase in CD4 counts at 12 months were CDC stage A-B, baseline HIV-RNA <105 copies/mL, absence of HBV/HCV coinfection, pursuit of the same cART during the first year, and initiation of cART after 2004. Treatments that followed the "what-to-start" guidelines were not independently associated with CD4 count variation at 12 months.Factors independently associated with an undetectable HIV-RNA at 12 months were CDC stage A-B, pursuit of the same cART during the first year, initiation of cART after 2006, and treatments following the "what-to-start" guidelines.Treatments that followed the "when-to-start" guidelines were not independently associated with cART modification, CD4 increase, or undetectable HIV-RNA at 12 months. The results of these different models are summarized in Table The objective of this study was to identify the relationship in daily practice between following treatment guidelines and the outcome within 1 year of initiating cART. Following the guidelines appeared overall satisfactory in this well-defined population of cART-naïve HIV-infected adults. However, 11% of patients were treated outside of the "when-to-start" guidelines and 11% outside of the "what-to-start" guidelines. Similar results have been observed in other European and Australian studies ,12]-[14-[1412]-,[11], buThe reasons for initiating treatment outside the guidelines appeared remarkably different when considering whether or not the "when-to-start" or "what-to-start" guidelines were followed. Patients initiating cART outside the "when-to-start" guidelines were typically young men having sex with men, less immunocompromised than the other patients, who initiate cART at a higher CD4 count level than those recommended at that time. Since the recommended CD4 count threshold has increased over time, patients starting cART above this threshold generally anticipated the following guidelines. Initiating treatment above the given CD4 count threshold was also observed in Danish and Australian studies ,15], wi, wi15], The 1-year outcomes were quite similar whether or not the "when-to-start" guidelines were followed. Not surprisingly, patients initiating treatment outside these guidelines had higher 12 month CD4 counts but lower CD4 increases than other patients. The virological efficacy was, however, identical between groups, and there was a similar rate of treatment modification during the first year of treatment. Therefore, neither a beneficial nor a detrimental evolution was observed after 1 year of follow-up in patients initiating treatment outside the "when-to-start" guidelines, whereas long-term differences could not be ruled-out in this study. Additionally, initiating cART earlier in these patients could have been associated with other benefits not measured in this study, such as a reduction in infectiosity and contagiousness.Following the "when-to-start" guidelines was better during the studied period than during the pre-cART (<1996) and early-cART eras (1996-1999), when the rapid evolution of knowledge led physicians to largely anticipate the guidelines . Similar3 in this study, whereas more patients initiated cART with CD4 counts between 200 and 350/mm3 in our study. However, the distribution of HIV viral load at initiation of treatment was similar between the 2 cohorts.Twelve-month outcomes were remarkably different regarding whether or not "what-to-start" guidelines were followed. Patients initiating cART outside of these guidelines had significantly worse immunological and virological outcomes and more treatment modifications during the first year than patients treated within these guidelines. A similar result was observed in the Swiss Cohort  in whichTreatments outside of the "when-to-start" guidelines were not associated with virological or immunological outcome at 12 months. Conversely, complex interactions were observed between treatment modifications during the first year, immunological and virological response at 1 year, and following the "what-to-start" guidelines. CDC stage C and the year of guideline publication were common predictors of all 12-month outcomes. Similarly, cART modification was negatively associated with an undetectable HIV-RNA at 12 months and with CD4 count increases from baseline. Female gender was associated with more treatment modifications during the first year, but was not associated with immunological and virological response. As previously reported ,26], HB, HB26], Limitations of this study include the follow-up that was voluntarily limited to 1 year in order to assess the effect of the first line of cART. Data on adherence and compliance were not collected, as well as associated comorbidities, which could have influenced the timing of cART initiation or the choice of drugs. A center effect could not be excluded, but the monocentric nature of the study allowed us to better characterize the predictors of outcome, since the study was less susceptible to heterogeneity in patient care than multicentric ones. Since the French guidelines for treating HIV infection are widely recognized in France, we referred to these guidelines rather than those of the IAS-USA or other international organizations, but we speculate that given the convergence of these guidelines over time, our conclusions would have been the same using a different set of guidelines. Excluding acute infection from the study could be another possible limitation since many physicians have been treating acute infection far before guidelines indicated to do so. However, since recommendations on the treatment of primary infection evolved with time, excluding acute infections provided homogeneity in our study population.In conclusion, initiating treatments that did not follow the "when-to-start" guidelines was related to cART initiation at higher CD4 counts than the recommended level at the time, mainly in young men who have sex with men, and was not associated with a significantly different 12-month outcome than observed in the same population during that period of time. Conversely, not following the "what-to-start" guidelines was not observed in any specific population and led to significantly worse virological outcomes at 12 months and more treatment modifications during the first year of cART. Efforts should be made to promote adherence to the "what-to-start" guidelines and to assess the adequacy of prescriptions within these guidelines.LC designed the study, collected the data, participated to data analysis and interpretation, drafted and revised the article. TB analyzed the data, participated to data interpretation and revised the article. PV designed the study, analyzed the data participated to data interpretation and revised the article. CB collected the data, participated to data interpretation and revised the article. TP collected the data, participated to data interpretation and revised the article. TF collected the data, participated to data interpretation and revised the article. CC designed the study, collected the data, participated to data analysis and interpretation and revised the article. All authors read and approved the final manuscript.


In many settings worldwide, members of indigenous groups experience a disproportionate burden of HIV. In Canada, there is an urgent need to improve HIV treatment outcomes for indigenous people living with HIV (IPLWH), to not only reduce HIV/AIDS-associated morbidity and mortality but also curb elevated rates of viral transmission. Thus, by comparing indigenous and non-indigenous participants in an ongoing longitudinal cohort of HIV-positive people who use illicit drugs, we sought to investigate longitudinal changes in three HIV treatment indicators for IPLWH who use illicit drugs during a community-wide treatment-as-prevention (TasP) initiative in British Columbia, Canada.We used data from the ACCESS study, an ongoing observational prospective cohort of HIV-positive illicit drug users recruited from community settings in Vancouver, British Columbia. Cohort data are linked to comprehensive retrospective and prospective clinical records in a setting of no-cost HIV/AIDS treatment and care. We used multivariable generalized estimating equations (GEE) to evaluate longitudinal changes in the proportion of participants with exposure to antiretroviral therapy (ART) in the previous 180 days, optimal adherence to ART (i.e. ≥95% vs. <95%) and non-detectable HIV-1 RNA viral load (VL <50 copies/mL plasma).p>0.1).Between 2005 and 2014, 845 individuals were recruited, including 326 (39%) self-reporting any indigenous ancestry, and contributed 6732 interviews and 13,495 VL measurements. Among indigenous participants, the proportion with recent ART increased from 51 to 94% and non-detectable VL from 23 to 65%. In multivariable models, later interview period was positively associated with recent ART (adjusted odds ratio (AOR)=1.16 per interview period, 95% confidence interval (CI): 1.11 to 1.20) and non-detectable VL . In adjusted models comparing indigenous and non-indigenous participants, we did not observe differences between the two groups (all In this large and long-term study involving community-recruited HIV-positive illicit drug users, we observed a substantial and increasing proportion of indigenous participants reach several important thresholds in HIV care at rates indistinguishable from non-indigenous participants. The current findings highlight the important role of TasP on vulnerable populations in this setting and contribute to the evidence base supporting the immediate scale-up of ART to address HIV/AIDS-associated morbidity, mortality and viral transmission. In many settings and among many groups, antiretroviral therapy (ART) has led to dramatic decreases in HIV/AIDS-associated morbidity and mortality among people living with HIV (PLWH) ,2. In adIt is estimated there are approximately 400 million indigenous people worldwide, living on all inhabited continents ,7. In geOver a decade ago, clinicians, policymakers and service providers in Vancouver, British Columbia, began implementing efforts to expand access and support adherence to ART among members of marginalized and vulnerable groups, through means such as simplified treatment algorithms, maximally assisted treatment programmes and harm-reduction-based out-patient centres, as part of an informal effort to promote TasP ,17–19. IFor these analyses, we used data from the AIDS Care Cohort to evaluate Exposure to Survival Services (ACCESS), an observational prospective cohort of HIV-positive illicit drug users. The study has been described in detail previously ,22. BrieFollowing study recruitment, all ACCESS participants complete an interviewer-administered survey that elicits information on lifetime and recent characteristics, behaviours and exposures. They also undergo an examination by a study nurse, including the provision of a blood sample for analysis. At recruitment, individuals provide their personal health number (PHN), a unique and persistent identifier issued for medical billing and tracking purposes to all residents of British Columbia. Using this identifier, study staff established a confidential linkage with the British Columbia Centre for Excellence in HIV/AIDS (BC-CfE) Drug Treatment Programme (DTP). Through the DTP, the BC-CfE provides HIV/AIDS treatment and care including all medications and clinical monitoring to all individuals living with HIV in BC through the province's no-cost universal medical system. A complete retrospective and prospective clinical profile is available for all ACCESS participants through this linkage. This profile includes all plasma VL observations and CD4 cell counts conducted through the study or as a part of ongoing clinical care, if any. In addition, this linkage contains records from the DTP's pharmacy, the province's sole source of HAART, including data on antiretroviral agent, dose and date dispensed for all HAART-exposed participants. Following the first interview, each participant completes a follow-up interview and nurse examination every 180 days. In these analyses, each interview period contains all the study interviews completed in specific and discrete 180-day calendar periods . Each individual could only be interviewed once in any interview period.For the current analyses, we included all individuals recruited between 1 November 2005 and 30 May 2014, who completed ≥1 study interview and had ≥1 plasma VL observation within ±360 days of their baseline interview. Among these participants, we included all baseline and follow-up interviews completed during the study period.In these analyses, the outcomes of interest were three measures of engagement in the HIV cascade of care: recent dispensation of HAART (yes vs. no), ≥95 adherence to prescribed HAART (yes vs. no) and plasma VL <50 copies/mL plasma (yes vs. no). We ascertained each outcome measure using information contained within each participant's comprehensive retrospective and prospective clinical monitoring records held at the BC-CfE. VL data were augmented by the results of serologic analysis of blood samples collected at each interview. For each period, we determined recent dispensation of HAART if there was a pharmacy record indicating the individual had picked up ≥1 day of HAART in the 180 days prior to the interview.As in previous research, we defined optimal adherence as ≥95% adherence to HAART in the previous 180 days. We calculated adherence as the ratio of the number of days of HAART dispensed in pharmacy records during the period to the number of days since an individual had initiated HAART, to a maximum of 180 days. We have previously demonstrated this validated measure of pharmacy refill data is strongly associated with plasma VL non-detectability and survival. Finally, for each period, we defined VL as the mean of all observations within the 180-day period prior to the interview dichotomized at <50 versus ≥50 plasma HIV RNA copies/mL.  was used to determine plasma VL from participant blood samples.) If there were no observations within the 180-day period prior to the interview, we declared that an individual had a detectable plasma VL unless they were HAART-exposed and pharmacy refill data indicated >95% adherence for the entire period.To compare treatment outcomes between indigenous and non-indigenous participants, our primary explanatory variable of interest was self-reported indigenous ancestry (yes vs. no). This variable was based on the baseline question: “What ethnic group or family background do you identify with?” All individuals who replied “First Nations,” “Aboriginal,” “Inuit,” “Métis” or reported any identification or affiliation with any specific indigenous group in Canada or the United States (e.g. “Mohawk” and “Cree”) were defined to have indigenous ancestry. To adjust for any underlying clinical differences between the indigenous and non-indigenous participants, we also considered a number of additional covariates including self-reported gender , age at baseline (per year older) and CD4 cell count (per 100 cells/mL). CD4+ cell count was time-updated and determined in the same manner as plasma VL. However, if any 180-day period lacked ≥1 CD4 observations, we used the most recent observation. We also included a covariate describing the interview period .As a first step, we compared socio-demographic and clinical characteristics of all participants at the baseline interview, stratified by indigenous ancestry. Next, to visualize changes in the outcomes of interest over time, we constructed plots of the proportion of indigenous and non-indigenous individuals satisfying each outcome of interest at each six-month interview period over calendar time. Our third step was to quantitatively test for differences in the proportion of indigenous and non-indigenous participants achieving each treatment threshold using generalized estimating equation (GEE) modelling. For each outcome, we estimated its relationship with indigenous ancestry and the other explanatory variables in bivariable models. Next, we fit multivariable models, each including one outcome of interest and all covariates.To assess possible changes in treatment outcomes among indigenous participants over time, we used the interview period as the primary explanatory variable. As above, we used bivariable and multivariable GEE models restricted to observations from indigenous participants to quantitatively assess the likelihood of experiencing each positive treatment outcome over time. To adjust for possible differences among indigenous participants, we included age, gender and CD4+ cell count in all three multivariable models.p=0.943).Between November 2005 and May 2013, 845 HIV-seropositive individuals were recruited, completed ≥1 study interview and had ≥1 plasma VL measurement within ±180 days of their baseline interview and were included in these analyses. Over the study period, the participants contributed 6732 interviews, or a median of 8 (interquartile range (IQR)=4 to 12) per participant, equal to 3366 person-years of follow-up. During this observation time, the participants completed 13,495 VL tests, or a median of 2 (IQR=1 to 3) per interview period. Of the 6732 180-day periods, 744 (11%) did not contain a VL test. This proportion did not differ by indigenous status , more likely to be non-male , with lower CD4+ cell counts at baseline . A similar proportion  of participants had ever been dispensed ART at baseline and in the previous 180 days . Although a significantly lower proportion of IPLWH attained ≥95% adherence , the prevalence of plasma VL non-detectability was indistinguishable  at baseline.The socio-demographic and clinical characteristics of the participants at baseline stratified by self-reported indigenous ancestry are reported in p=0.057); the interaction terms in the analyses of ART adherence and non-detectable VL were not significant (p>0.5).The results of the longitudinal analyses of difference between indigenous and non-indigenous participants are presented in In this study, we observed significant and substantial increases over time in the proportion of IPLWH who use illicit drugs achieving important thresholds in HIV treatment and care. An increasing proportion of indigenous participants were engaged in care, reflected by recent dispensation of ART, increasing from 56 to 93% during the study. In addition, almost two-thirds of indigenous participants achieved non-detectable VL by the end of the study, compared with less than one-quarter at study start (23 vs. 65%). These changes were observed in separate longitudinal multivariable models adjusted for gender, age and CD4 cell count. Both the magnitude of the improvements and their rate of change were indistinguishable between indigenous and non-indigenous participants.p=0.001) [These findings stand in sharp contrast to previous studies from the earlier era of HIV treatment in this setting, and others which have described important disparities in ART access and outcomes between indigenous and non-indigenous individuals ,23–31. Mp=0.001) ,28,29,32p=0.001) . It is ip=0.001) . Thus, fThe substantial decrease observed in the proportion of indigenous individuals with detectable plasma VL in this study has implications not only for disease progression among these individuals but also for patterns of viral transmission. Both randomized clinical trials  and obseOur findings have immediate implications for policy and practice. First, while we observed impressive improvements in three key measures of HIV care among a traditionally under-treated group, a substantial proportion of indigenous and non-indigenous individuals continue to experience sub-optimal treatment outcomes. Renewed emphasis should be placed on addressing the social and structural barriers to effective ART, including homelessness , high-riThis study has limitations. First, there is increasing awareness of the importance of indigenous-led systems to identify indigenous individuals, especially in government and research data, in decolonization and self-government efforts . In addiTo conclude, we sought to evaluate longitudinal changes in HIV treatment indicators among indigenous people who use illicit drugs during a community-wide TasP intervention in British Columbia, Canada. Between 2005 and 2013, we observed significant and substantial increases in the proportion of individuals with recent dispensation of ART, achieving optimal adherence to ART and attaining non-detectable levels of plasma VL. These results not only describe impressive clinical achievements by these individuals but also support the immediate scale-up of efforts to engage indigenous individuals in HIV treatment and care as a means to reduce elevated levels of HIV/AIDS-associated morbidity, mortality and viral transmission.


In 2011 Uganda recommended boosted atazanavir (ATV/r) as the preferred PI for second line due to once daily dosing, replacing aluvia (LPV/r) . There aRetrospective cohort analysis on routinely collected data of patients switched to second line with NRTI backbones TDF/3TC or FTC, AZT/3TC, ABC/3TC from January 2009 to December 2013. Students T-tests and Chi-square tests were used in this analysis.A total of 1286  patients were switched to LPV/r 991 (77%) and ATV/r 295 (23%) (p<0.001). NRTI backbones were 760 on TDF/3TC (66.8% LPV/r vs 33.2% on ATV/r), 504 on AZT/3TC (93.3% vs 6.7%), and 22 on ABC/3TC (59% vs 41%). Median (IQR) time on first line for LPV/r was 21 (1–44) months and for ATV/r was 41 months (22–68). Median CD4 (IQR) at switch to LPV/r was 181 cells/uL (66–424) and to ATV/r was 122 (57–238) (p≤0.001). A total of 366 patients had CD4 done at six months after switch and the mean (IQR) CD4 increase was 153 (54–241) for LPV/r versus 116 (52–171) for ATV/r (p=0.232). Additionally, 304 had a CD4 at 12 months and the means were 172 (45–272) for LPV/r vs 179 (60–271) for ATV/r (p=0.426). There was no significant difference in the mean increment by NRTI backbone or by stratifying to viral load (VL) at time of switch to VL <100,000 and ≥100,000. Median (IQR) VL at switch was 61,000  LPV/r and 51,000  ATV/r. 269 had a VL done in the first 12 months and 178/250 (71.2%) on LPV/r versus 16/19 (84.2%) on ATV/r were undetectable (p=0.228). 259 (26%) LPV/r versus 33(11%) ATV/r had ≥1 opportunistic infections on second line (p<0.001).This is an observational study based on our experience at IDI. Like elsewhere in Africa, there is no routine viral load testing, making it difficult to get sensitive analysis of data on ART efficacy within routine clinical practice. Nevertheless, this observational study is reassuring in terms of efficacy of both ATV/r and LPV/r for patients failing first line therapy in our setting.


Rapid scale-up of antiretroviral therapy rollout in Sub-Saharan African countries faces the challenge of virological failure. This could be the consequence of transmitted drug-resistant human immunodeficiency virus strains at the population level. While a pre-antiretroviral therapy genotypic test has been a major component of the human immunodeficiency virus management programme in developed nations, it is yet to be incorporated into the antiretroviral therapy programme in resource-poor countries.® (lopinavir and ritonavir). A human immunodeficiency virus drug genotypic testing showed she was only susceptible to zidovudine and protease inhibitors. At third month on the new regimen, her viral load was suppressed.A 32-year-old Black African woman was seen for her six-month routine review. Her viral load after initiation of fixed drug combination of tenofovir, emtricitabine and efavirenz was 31,397 RNA copies/mL. Adherence was assessed to be good based on pharmacy pick-up dates, on-time clinic appointment records, medical file review, self-reporting and treatment supporter’s report. Her viral load was repeated after another two months of close monitoring; the result showed viral load of 31,159 RNA copies/mL. She was assessed as virological failure to her first-line antiretrovirals and commenced on second-line antiretrovirals: zidovudine/lamivudine/AluviaThis case report demonstrates the possibility of a silent epidemic within the human immunodeficiency virus pandemic in resource-poor settings like Eastern Cape, South Africa. We described a case of early virological failure in a highly motivated young woman. Although, a pre-antiretroviral therapy genotypic test is yet to be incorporated into a human immunodeficiency virus programme in resource-poor countries, the need for it might become evident as the programme expands. Close monitoring of the viral load of patients according to national guidelines will enable early detection of a failing regimen and prompt intervention can be instituted to prevent morbidity and mortality. There is an urgent need to strengthen the human immunodeficiency virus programme in resource-poor countries to prevent the emergence of an epidemic of transmitted drug-resistant human immunodeficiency virus strains within the existing human immunodeficiency virus pandemic. According to the 2013 Global Report of the Joint United Nations Programme on HIV and AIDS (UNAIDS), 35.3 million people were living with human immunodeficiency virus (HIV) by the end of 2012 and 70.8% of the global burden reside in Sub-Saharan Africa. South Africa has the highest burden of the HIV epidemic (6.4 million people living with HIV/acquired immunodeficiency syndrome) . Ho. Hoet alIt remains a challenge that a pre-ART genotypic resistance testing could not be undertaken in patients with HIV infection in a resource-constrained setting as this would have provided information on the baseline ARV drug resistance. Also, the inability to conduct ARV drug levels in the partner of the patient should be noted.Although, a pre-ART genotypic test is yet to be incorporated into an HIV programme in resource-poor countries, the need for its incorporation into clinical care may become more evident as the prevalence of TDR rises. Meanwhile, close monitoring of VL of patients according to the national guidelines is very important. This will enable early detection of a failing regimen and prompt intervention can be instituted to prevent accumulation of resistant strains, virological failure, morbidity and mortality. There is an urgent need to strengthen the HIV programme in resource-poor settings to prevent the emergence of a silent epidemic of TDRHIV within the HIV pandemic.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


Very scarce information has been published to date with the combination of ABC/3TC/NVP but it is currently being used in clinical practice in Spain and Portugal. Our aim was to present the clinical experience with this regimen in a cohort of adult HIV-infected antiretroviral (ARV)-naïve patients.Retrospective, multicentre, cohort study. Consecutive adult HIV-infected ARV-naïve HLA-B*5701-negative patients, who started ABC/3TC/NVP between 2005-2013, with at least one follow-up visit, were included. Demographic, clinical and laboratory variables were assessed at baseline, month 1, and every three–four months thereafter. The primary end point was HIV-1 viral load (VL)<40 c/mL at 48 weeks. Data were analyzed by intent-to-treat (ITT)  and on treatment (OT) analyses.78 patients were included. Median follow up was 26 (0.1-84) months. 86% were male, median age 41 (23-69) years, 9% had AIDS, 8% were HCV+, baseline CD4 was 275 (10-724) cells/µL and median VL 4.58 (3.02-6.92) log. After 48 weeks, VL was<40 c/mL in 89.8% (OT), 79.7% (M=F) and 65.4% (S=F) and at 96 weeks in 88.5%, 78.9% and 61.6%, respectively. CD4 increased +246 (p<0.001) and +292 (p<0.001) cells/uL after 48 and 96 weeks, respectively. One or more drugs of the regimen were discontinued in 33 (42.3%) patients. In 15 (19.2%) patients  therapy was stopped due to toxicity after a median of one month (in only two cases after six months of follow up): 80% of them had rash/liver toxicity. Six (7.7%) patients discontinued ART due to virologic failure, five (6.4%) because of other reasons and seven (9%) were lost to follow-up. ALT but not AST significantly increased . A significant increase of 25%, 26% and 42% in total cholesterol, LDLc and HDLc, respectively, and a significant decrease in TC/HDL ratio  was observed after 96 weeks.Despite a considerable proportion of patients had to stop therapy due to toxicity (most associated with NVP), those initially tolerating this regimen presented a high virologic and immunologic response after 96 weeks, as well as a favourable lipid profile. ABC/3TC/NVP may be a suitable alternative first regimen, mainly in countries with economic constraints.


Timely detection of treatment failure with subsequent switch to second-line regimen reduces mortality among HIV infected people on antiretroviral therapy (ART). This paper aims to investigate the detection of immunological treatment failure and switch rate to second line regimen in Ethiopia.A retrospective cohort study was conducted among HIV infected patients (age > 15 years) who initiated ART between 2007 and 2009. The required data were collected from patient registers and formats. Data were entered and validated using EpiData software and then exported to SPSS version 20.0 for analysis. Odds ratio with 95 % CI was used to assess whether immunological treatment failure was associated with experiencing unfavorable treatment outcomes (death or lost to follow up).3 (IQR: 64–176). A total of 46 (15.7 %) patients experienced immunological treatment failure. The immunological failure rate was 3.0 per 100 PYO. Treatment was switched to second-line regimen for six (2.1 %) patients. The rate of treatment switch to second-line regimen for any purpose was 0.4 per 100 PYO. Out of the six patients, only two fulfilled the WHO criteria for immunological failure; the remaining four patients had their treatment switched to second-line regimen for other purposes. This implies that only 4.3 % (2/46) of patients with immunological failure were switched to second-line regimen. The risk of experiencing unfavorable outcome was 5.75  times higher among those who had immunological failure than their counterparts after adjusting for baseline CD4 count.Records of 293 patients were reviewed with a total of 1545 Person-Years of Observation (PYO). The median baseline CD4 count was 115 cells/mmMajority of patients with immunological treatment failures were not detected and continued taking the failed regimen. Further studies are required to assess and explore why patients with immunological failure are not switched to second-line regimen as per the standard protocol. Approximately 35.0 million people were living with HIV in the world by the end of 2013. In the same year, 12.9 million people living with HIV were receiving antiretroviral therapy (ART) globally, out of which 11.7 million were in low and middle-income countries representing 36 % of the 32.6 million people living with the virus in low and middle-income countries [As the ART uptake increases, the emergence of resistant viruses resulting in treatment failure is inevitable and should be anticipated proactively. As a result patients need to be switched to second-line regimen in order to have a sustained viral suppression –3.3 [The diagnosis of treatment failure is guided by viral load testing in high income countries; however, this is not the case in most low income countries because viral load testing is costly and requires advanced infrastructures , 3. CognEven though the immunological criteria to diagnose treatment failure was documented to have low positive predictive value and low sensitivity, the extent to which it is being utilized in health facilities has not been well studied in Ethiopia. Thus, in this study we aim to investigate the rate of immunological failure, its detection and switch rate to second-line regimen.The study was conducted in Federal Police Referral Hospital (FPRH). ART program was launched in the hospital in parallel with other public health facilities. FPRH started to provide ART service in 2005. The hospital also provides HIV prevention, care and support services.The ART guideline in Ethiopia is based on the 2008 WHO recommendations. However, there were technical updates as an addendum to the national ART guideline at different times based on the 2010 and 2013 WHO recommendations .According to the national ART guideline, eligibility for initiation of ART is determined using CD4 count and WHO clinical stage. When CD4 count is not available, patients with WHO clinical stage III and IV conditions are eligible for treatment. In addition, patients with WHO clinical stage II conditions with Total Lymphocyte Count (TLC) less than 1,200 cells/ml are considered for treatment [3 and all patients with WHO clinical stage IV conditions are eligible for treatment. In addition, patients with WHO clinical stage I and II with CD4 cell count below 200 cells/mm3 are eligible for treatment [Whereas in the presence of CD4 count, WHO clinical stage III patients with CD4 cell count less than 350 cells/mmIn FPRH, the HIV chronic care services are delivered by trained nurses and health officers. Physicians are available for consultation in case of complications and for patients with advanced disease.This study was a retrospective cohort study of HIV-infected patients who started ART at the FPRH. The intended service users in FPRH include active and retired police members, their dependents, civilian workers and other civilian residents in the surrounding area.The current study included patients (age > 15 years) who started ART between January 2007 and December 2009, had follow up in the facility for at least 24 months and had at least four CD4 measurements including the baseline measurement. Transfer-in cases were also included in the study provided that they fulfilled all the other inclusion criteria. The primary end-point was immunological failure using the WHO definitions as outlined above.In the present study, baseline CD4 count was a measurement occurring closest to the date of starting ART, within a window of 6 months prior to the start of ART to 1 week after ART initiation.A structured data abstraction format was used to collect the data from patients’ cards and registers. The format was developed using the standardized patient monitoring formats and registers. Patient intake form, follow up card and ART registers as well as the electronic information database were used as data sources. Other clinical charts including laboratory test results were also used to collect the CD4 cell counts.Unique ART number and the new Health Management Information System (HMIS) card number were used to identify individual patient cards or their data in the electronic database. Socio-demographic characteristics, baseline and follow up clinical and laboratory data, and treatment outcomes were collected from patient cards.Two data clerks and one case manager (adherence supporter) from FPRH were trained and hired as data collectors. The federal police health service directorate data manager was hired as data collection supervisor. All completed formats were examined for clarity and consistency by the supervisor and finally by the researchers. The data were collected in June /2014.Data were entered, and validated using EpiData software version 3.1. Each format was given a unique identification number for data entry. A cleaned and compiled data were exported for analysis to SPSS version 20. Proportions, means, medians with measures of dispersion were calculated as deemed necessary. Odds ratios with 95 % CIs were used to assess whether immunological treatment failure was associated with experiencing unfavorable treatment outcomes (death or loss to follow up). For statistical tests, level of significance was set at type-I error of 0.05.Ethical clearance was obtained from Addis Continental Institute of Public Health and Mekele University joint Institutional Review Board. Permission was obtained from Federal Police Health Service Directorate and FPRH administration. In Ethiopia, patients are not requested for consent to use an already existing data within health facilities. All the information obtained during the course of the study was held in a confidential manner. The data were kept in a locked cupboard. Patient names were not recorded or linked to the results of the study.Within the period of interest, there were a total of 741 patients who initiated ART in the hospital. However, only 293 charts fulfilled the inclusion criteria and were included for data abstraction. Figure 3 (IQR: 64–176). Majority (75.8 %) of the patients had baseline CD4 count less than 200cells/mm3. In relative terms, the common regimen was D4T/3TC/NVP accounting for 39.2 %. Treatment was switched to second-line regimen for 2.1 % of the cases. Substitution to different drugs within first line regimen was observed for 30.7 % of the cases. Similar results for other variables and disaggregated by immunological failure status is shown in Table Records of 293 patients were reviewed with a total of 1545 Person-Years of Observation (PYO). All the study cohorts initiated treatment between January 2007 and November 2009. Most (58.4 %) of the study cohorts started ART in the month of knowing their HIV infection status. At baseline, the mean age was 36.7 years (SD = 8.6 years) and 64.2 % were males while the sex of 0.7 % were not recorded. The median baseline CD4 count was 115cells/mmThe median retrospective follow up period was 70 months (IQR: 54–76 months). By the time the data collection terminated, 81.2 % were actively on treatment, 4.1 % were lost or dropped from care, 2.0 % died and the rest 12.6 % were transferred out to another facility.A total of 46 (15.7 %) patients experienced immunological treatment failure. This translates to immunological failure rate of 3.0 per 100 PYO. Out of these 46 patients with immunological failure, the reasons for the failure were drop by more than 50 % of the pick value attained in 45.3 % of the cases, persistently below 100 cells/mm3 after taking ART for at least 24 weeks in 13.3 % of the cases and CD4 count below the baseline value in another 45.3 % of the cases.Treatment was switched to second-line regimen for six (2.1 %) patients. The rate of treatment switch to second-line regimen for any purpose was 0.4 per 100 PYO. Out of the six patients only two fulfilled the WHO criteria for immunological failure; the remaining four patients had their treatment switched to second-line regimen for other purposes such as regimen simplification. This implies that only 4.3 % (2/46) of immunologically failed patients were switched to second-line regimen.Next we examined if immunological treatment failure was associated with final follow up status. Accordingly, we found that the proportion of patients experiencing unfavorable treatment outcome was higher among patients with immunological treatment failure than their counterparts. For instance, the proportion of those who died was 6.5 % among patients who had immunological failure whereas it was 1.2 % among the other group  times higher among those experiencing immunological failure than their counterparts and it became 5.75  times higher when adjusted for baseline CD4 count.In the present study, it was found that after a median follow up duration of 70 months (IQR: 54–76 months), 15.7 % of the cohorts experienced immunological failure. The failure rate of 3.0 per 100 PYO observed in our study was slightly less than a study conducted in Haiti which reported failure rate of 4.8 per 100 PYO [The overall switch rate to second-line regimen of 2.1 % in the current study is very low when compared with other studies from resource-constrained settings –10. ThesThe collaborative analysis of data from Zambia and Malawi documented the overall switch rate of 13.4 % among patients with immunological failure ; howeverIn this study, around 96 % (44/46) of patients with immunological failure continued to take the already failed first-line regimen. This finding was significantly different from the report from Haiti where the health care systems detected 40 % and subsequently switched treatment to second-line regimen . This inIn the current study, we noted that the risk of unfavorable outcome was significantly higher among immunologically failed group. As this is a facility based document review study, we couldn’t further verify the outcomes of those who were lost from care. In order to control for this, if we make the assumption that all patients who were lost from care are alive, the risk of dying remains significantly higher though the confidence interval becomes wide owing to the sample size . Previous studies conducted in Malawi to verify the true outcome of lost patients indicated that around half of such patients were found to be dead and remained undocumented by the health system , 16.OtheDiagnosis of treatment failure and timely regimen switch to second-line may also act as a positive push factor for prevention of circulation of resistant viruses in the community. A study conducted by Reynolds et al. found that patients with immunological failure exhibit several types of mutations . The conFinally, the study may have limitations which could affect generalization for the whole population on treatment. In the first place many patients were excluded from the cohort because their charts weren’t accessible and/or they didn’t fulfill the inclusion criteria of having at least four CD4 count measurements Kiraga et al.  in a recIn the current study, it was observed that majority of patients with immunological treatment failures were not detected and such patients continued to take the failed regimen. The proportion of unfavorable outcome was higher among the immunologically failed group. Further studies are required to assess and explore why patients with immunological treatment failure are not switched to second-line regimen as per the standard protocol.Not applicable.


While the prevalence of X4-tropic viruses in subtype B is relatively well studied the distribution of tropism in CRF06_cpx (causing Estonian epidemic) is less known, especially in the treatment experienced patients with established multidrug-resistance and who are candidates for therapy with CCR5 antagonist.Aim: to describe HIV-1 drug resistance mutations (DRMs) and co-receptor tropism in antiretroviral (ARV) treatment failing patients infected with HIV-1 CRF06_cpx and to establish their suitability to treatment with CCR5 receptor antagonists.[coreceptor] 2.5. algorithm, respectively. All sequence prediction results with a false-positivity rate above 10% were considered R5-tropic.Altogether 12 patients were studied – all with ARV therapy failure and considered to start CCR5 antagonist therapy. Genomic viral DNA was directly sequenced in pol region and V3 loop of gp120 in triplicates. HIV-1 DRMs and tropism were detected using Stanford University Drug Resistance Database and Geno2phenoOf 12 viruses 11 were successfully sequenced and analyzed. Patients have been diagnosed and ARV therapy initiated in 2002-2013. 8/11 cases had failure of the second ARV regimen, 4/11 of the third and in 2/11 of the fourth ARV regimen. Median viral load at the time of tropism testing was 53,326  and median CD4+ count 184 (IQR 142-217) cells/cmm. The most commonly used regimens were EFV + 3TC plus AZT (5 cases) or plus ABC (4 cases). Of 11 viruses 10 had resistance against two ARV classes (NRTI + NNRTI or NNRTI + INI) and 1 had triple class resistance (NRTI + NNRTI + PI). In NRTI treated population the most common primary DRM was M184V (10/11), followed by L74V/IL/I and K70E/R/EKQ (both 4/11). In NNRTI treated population DRMs were as follows: K103N (5/11), P225H (4/411), G190A/S and K101H/E (both 3/11), others were seen in lower frequency. In PI treated patients two primary DRMs were represented – I54V, V82A (both in same case). In INI treated population one primary DRM was represented – Y143R. The majority of viruses (10/11) were R5-tropic and all determined as CRF06_cpx by phylogenetic analysis.The Estonian HIV epidemic has reached the stage where the first patients are considered to start treatment with CCR5 antagonists. Almost all highly resistant viruses were R5-tropic suggesting that CCR5 antagonists are an appropriate option for CRF06_cpx viruses resistant to other ARV agents.