Combination therapy in managing psychiatric disorders is not uncommon. While combination therapy has been documented for depression and schizophrenia, little is known about combination therapy practices in managing attention-deficit/hyperactivity disorder (ADHD). This study seeks to quantify the combination use of ADHD medications and to understand predictors of combination therapy.Prescription dispensing events were drawn from a U.S. national claims database including over 80 managed-care plans. Patients studied were age 18 or over with at least 1 medical claim with a diagnosis of ADHD , a pharmacy claim for ADHD medication during the study period July2003 to June2004, and continuous enrollment 6 months prior to and throughout the study period. Dispensing events were grouped into 6 categories: atomoxetine (ATX), long-acting stimulants (LAS), intermediate-acting stimulants (IAS), short-acting stimulants (SAS), bupropion (BUP), and Alpha-2 Adrenergic Agonists (A2A). Events were assigned to calendar months, and months with combined use from multiple categories within patient were identified. Predictors of combination therapy for LAS and for ATX were modeled for patients covered by commercial plans using logistic regression in a generalized estimating equations framework to adjust for within-patient correlation between months of observation. Factors included age, gender, presence of the hyperactive component of ADHD, prior diagnoses for psychiatric disorders, claims history of recent psychiatric visit, insurance plan type, and geographic region.There were 18,609 patients identified representing a total of 11,886 months of therapy with ATX; 40,949 months with LAS; 13,622 months with IAS; 38,141 months with SAS; 22,087 months with BUP; and 1,916 months with A2A. Combination therapy was present in 19.7% of continuing months (months after the first month of therapy) for ATX, 21.0% for LAS, 27.4% for IAS, 23.1% for SAS, 36.9% for BUP, and 53.0% for A2A.For patients receiving LAS, being age 25–44 or age 45 and older versus being 18–24 years old, seeing a psychiatrist, having comorbid depression, or having point-of-service coverage versus a Health Maintenance Organization (HMO) resulted in odds ratios significantly greater than 1, representing increased likelihood for combination therapy in managing adult ADHD.For patients receiving ATX, being age 25–44 or age 45 and older versus being 18–24 years old, seeing a psychiatrist, having a hyperactive component to ADHD, or having comorbid depression resulted in odds ratios significantly greater than 1, representing increased likelihood for combination therapy in managing adult ADHD.ATX and LAS are the most likely drugs to be used as monotherapy. Factors predicting combination use were similar for months in which ATX was used and for months in which LAS was used except that a hyperactive component to ADHD predicted increased combination use for ATX but not for LAS. Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder that originates in childhood and often continues into adulthood. It has been estimated that between 3% and 10% of all children are affected by ADHD and that 33% to 66% of these children have ADHD symptoms into adulthood  and is oMedications are commonly used to manage ADHD. Most often used are stimulants that interact with brain monoamine systems. These include amphetamines  and methylphenidate . Nonstimulant medications include atomoxetine (Strattera) and bupropion (Wellbutrin) . StimulaPolypharmacy (combination therapy) in managing psychiatric disorders is not uncommon -17. IndeThe purpose of the present study is to examine the prevalence of combination therapy in adults with ADHD using a retrospective claims analysis of data from a large data warehouse. These data are also used to determine which demographic or utilization patterns, if any, predict combination therapy in adult ADHD patients receiving either long-acting stimulants or atomoxetine. We focus on these medications as they represent the most comparable treatments in terms of duration of action and represent the newest additions and possibly most costly therapies. Note that our perspective is not clinical. We make no claims or recommendations regarding the effectiveness of combination therapy or the tradeoffs in terms of cost or increased exposure to potential side effects of medication. Instead, our research is an examination from the health systems perspective, where combination use may be seen as duplicative or an indication that existing resources are not being used to maximal effect.This study was a retrospective claims analysis of data obtained from the commercially available PharMetrics, Inc. data warehouse on October 6, 2005. Medication usage was analyzed for the period from July 2003 to June 2004. These data reflect U.S. national medical and pharmacy claims covering more than 80 managed-care organizations and 60 million beneficiaries. All data received had been previously de-identified so as to maintain the confidentiality of patients. This study was conducted in compliance to all requirements of the Health Insurance Portability and Accountability Act (HIPAA).The initial subset drawn included all patients  with at least 1 medical claim with a diagnosis of ADHD (ICD9-CM code 314.0). We narrowed the focus to patients who were enrolled 6 months prior to and throughout the study period . From these, we identified patients 18 years or older in 2003 . Finally, we determined which of those patients had a prescription for an ADHD medication during the study period . This was the basis for our final analysis group. It is important to note that while demographics are given for the individuals included in the study, the unit of analysis is patient-months during which individuals received a prescription for an ADHD medication.Data were analyzed as patient-months of treatment on any given class of medication, and each calendar month of treatment was characterized as being associated with either monotherapy or combination use of medications. Patient-level claims were assigned based on the date of service and days' supply. Supplies of less than or equal to 31 days were assigned to a single month; supplies of 32 to 60 days, to 2 months; and 61 to 90, to 3 months and so on. The starting month was taken to be the month of the claim if a greater portion of the supply was available in that month than in the last succeeding month covered by the claim. Otherwise, the starting month was shifted to the month immediately following the claim date. In addition, to focus on long-term combination therapy rather than details of transitional management , the first month of each continuous treatment episode was excluded from analysis.As shown in Table We determined the predictors of combination therapy separately for LAS and ATX in those patients covered by commercial plans. To adjust for correlation within the months of treatment in the same patient, logistic regression was performed in a general estimating equations framework with exchangeable covariance structure between months within patient. Factors included in the models were age, gender, presence of hyperactive component to the ADHD, prior claim diagnoses for various psychiatric disorders, claims history of prior psychiatric visit, insurance plan type, and geographic region. Diagnoses were considered positive if seen in 2 claims on separate days in the 6 months prior to study period, and psychiatric service use was considered positive if seen in 1 claim prior to study period.® system version 8.02 for Unix  with predictive models fit using PROC GENMOD. Confidence intervals are reported at the 95% level.Analyses were performed using the SASDemographic characteristics of patients contributing prescription events are presented in Table Total patient months of LAS, IAS, or SAS treatment were 40,949; 13,622; and 38,141, respectively. Total patient months of the nonstimulants – ATX, BUP, or A2A – were 11,886; 22,087; and 1,916, respectively. Of these, 34,239; 11,200; 31,239; 8,141; 18,318; and 1,639 were months following the first months of usage for each medication class , patients received medication combinations 21.0% of months for LAS, 27.4% of months for IAS, and 23.1% of months for SAS ; LAS, most frequently with SAS (9.5% of months); IAS, with SAS (17.1% of months); and SAS with LAS (9.1% of months).Adjusted odds ratios for various factors predicting whether a given month of therapy would be a month in which multiple medications were received are presented in Figure For patients receiving LAS, being age 25–44 or age 45 and older versus being 18–24 years old, seeing a psychiatrist, having comorbid depression, or having point of service coverage versus a Health Maintenance Organization (HMO) resulted in odds ratios significantly greater than 1, representing increased likelihood for combination therapy in managing adult ADHD.For patients receiving ATX, being age 25–44 or age 45 and older versus being 18–24 years old, seeing a psychiatrist, having a hyperactive component to ADHD, or having comorbid depression resulted in odds ratios significantly greater than 1, representing increased likelihood for combination therapy in managing adult ADHD.The results of the present study indicate that combination therapy in adult ADHD is not uncommon. Combination therapy was present in more than 20% of the months of therapy represented in this sample. Approximately 8–9% of the combination therapy of stimulants and of ATX was with BUP. This may not represent true combination therapy for treatment of ADHD but may rather reflect treatment of comorbid conditions, particularly depression.Combination therapy was least common in patients prescribed LAS and in patients prescribed ATX. For patients prescribed BUP or A2A, combination therapy was much more common. Interestingly, for patients prescribed BUP and A2A, the supplemental medications were most often stimulants.The finding that combination therapy is not as common for patients prescribed stimulants relative to BUP and A2A, despite that these medications were the class most often prescribed is consistent with the use of these indicated drugs as "first line" agents for adult ADHD . BUP andIAS showed markedly more combination use with SAS than either LAS or ATX. This may reflect the more limited duration of action of IAS being insufficient to maintain adequate ADHD symptom control throughout the entire day.To better understand the factors that contributed to combination therapy in patients prescribed long-acting ADHD medications, specifically LAS and ATX, we calculated odds ratios for combination therapy from patient characteristics. A number of these factors were associated with combination therapy. These included being older, having psychiatric care, and having comorbid depression. The association between psychiatric care and combination therapy is not surprising given that patients with more severe or treatment refractory disease are more likely to be referred for psychiatric care after having failed 1 or more simpler treatment regimens.In contrast to previous models where the decision to initiate ATX rather than LAS was associated with claims histories suggesting high comorbidities and clinical complexity , the patAs described above, combination therapy in adult psychiatry is not uncommon and is fairly well documented in depression and schizophrenia -17. CombThe management of patients with adult ADHD can be complex. In making treatment decisions, clinicians must evaluate the unique characteristics of patients as well as the distinct benefits and risks of different treatment options. For example, although stimulants are very effective in treating ADHD, they have significant abuse potential ,19. In pAlthough these findings provide initial data on combination therapy in adult ADHD, several limitations need to be acknowledged. Claims data are collected for administrative purposes and cannot be considered as accurate or reliable as data collected for a specific scientific purpose. Second, the provider type "psychiatrist" is imputed within the PharMetrics database and may include some psychologists and social workers billing for services typical of psychiatrists. The attribution of a claims history of prior psychiatric visit is, therefore, somewhat imprecise. Third, formulary status, plan restrictions, and tier status were not known and may have influenced the associations described here. Fourth, although these data indicate that LAS and ATX are least likely to be associated with combination therapy in ADHD, direct evidence of effectiveness  is not available in this dataset. Fifth, from the perspective of generalizability, patients from the Midwest and South are overrepresented in this sample, so care should be taken in generalizing too broadly. Finally, although the sample was restricted to patients with a previous claim diagnosis of ADHD, one is not able to conclusively determine the reason for each individual pharmaceutical claim.This study suggests that only a small percentage, 6.1% of the adult patients with a history of ADHD, receive any pharmacological treatment during the course of a year. LAS and ATX are the most common pharmacological monotherapies in the treatment of adult ADHD. IAS and SAS were used more frequently in combination with other medications while BUP  and A2A  were most often to be used in combination with other medications. Factors predicting combination use  were similar for months in which ATX was used and for months in which LAS were used, except that a hyperactive component to ADHD predicted increased combination use for ATX but not for LAS. Further research is needed to better understand the motivations for combination therapy in managing adult ADHD, particularly in terms of symptom outcomes and nonpharmacological treatments used for ADHD.Of the 5 authors, 4 are employees of Eli Lilly and Company, and the fifth author is a consultant to Eli Lilly and Company.GMP contributed to the design, analysis, interpretation, writing, and review of the manuscript. DVB contributed to the design, interpretation, writing, and review of the manuscript. WY contributed to the analysis, interpretation, and review of the manuscript. WWS contributed to the interpretation, writing, and review of the manuscript. JAJ contributed to the design, interpretation, and review of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The efficiency of antiretroviral therapy (ART) depends on a near perfect level of patients' adherence. The level of adherence of adults HIV-infected patients treated in the HIV/AIDS health care centres of the association "Espoir Vie Togo" in Togo, West Africa is not properly documented. The aim of the present study was to examine by means of self-reports the knowledge, the adherence level and associated factors to antiretroviral therapy (ART) among these patients.We conducted a cross-sectional survey among adult people living with HIV/AIDS (PLWHA) through a structured questionnaire.A total of 99 patients were enrolled. Among them, 55.6% knew the name of antiretroviral agents of regimens prescribed. All patients had a good knowledge of treatment schedule. The treatment regimens based on 2 NRTIs + 1 NNRTI were used in 90% of patients. The average adherence rate was 89.8% of the total doses prescribed while 62.62% of patients showed an adherence rate of 95% or above. The treated groups were similar in term of median % of medication doses taken according to PLWHA epidemiological characteristics. However, patients reported forgetting (34.9%), travel (25.6%), cost of treatment (13.9%) and side effects (11.6%) as the main factors of missing at least once a dose intake.These results should encourage the association and all the involved actors in the HIV/AIDS's program to strengthen counseling, education and information interventions for HIV-infected patients in order to overcome the potential barriers of poor adherence. Since 1996, progress in the field of antiretroviral therapy has led to the reduction of about 80% of deaths, the number of cases of acquired immunodeficiency syndrome (AIDS) and the incidence of opportunistic infections ,3. The lCohorts followed up in developed countries have emphasized the frequency of non-adherence situations, the high level of adherence required to obtain optimal efficiency of ARVs chemotherapy, and delay the beginning of the human immunodeficiency virus (HIV) resistance and pejorative evolution of the disease ,16.The assessment of adherence, parameter that has no standard method of measurement, which varies over time, meets a number of methodological difficulties . Few stuThe present study was a cross-sectional survey carried out during the months of August and October 2005 in the HIV/AIDS health care centers (in urban areas of Lomé and Sokodé) of the association "Espoir Vie Togo" (EVT), the first organized non-governmental organization of people living with HIV/AIDS and those contributing to their support. The association is recognized by National HIV/AIDS Control Programme "Programme National de Lutte contre le SIDA" (PNLS-Togo) as an ambulatory HIV/AIDS health care association. The association is also involved in the purchasing of ARVs for its members from the "Centrale d'Achat de Médicaments Essentiels et Génériques" (CAMEG-Togo). The ARVs are supplied to the patients, in EVT's pharmaceutical stores.We interviewed eligible HIV-infected adults when they came to EVT's pharmaceutical stores to receive their monthly supply of ARVs. The enrolment was done on a voluntary basis.To be enrolled in the study, HIV-infected patients have to meet the following criteria: all adult patients over 15 years, the members of EVT association placed on ARVs therapy for over 1 month, who receive ARVs in EVT pharmaceutical stores. Hospitalized patients and those whose age is below 15 years were excluded from the study.A cross-sectional survey was conducted from a structured questionnaire  and ARVs procurement;- The patient treatment knowledge which was assessed through the knowledge of the names of the various drugs prescribed their respective dosages (number of tablets per dose and number of daily intakes) and the times of intake. The statements of patients were compared with the prescriptions and the treatment regimens mentioned in their health card;-The type of ARVs combination regimens prescribed;- The rate of adherence to treatment by means of self-reporting: It was assessed in the last month and defined as the number of doses taken during the last 7 days before each interview. Adherence score was expressed as the proportion (%) of tablets taken compared to prescribed tablets. An adherence rate of 95% or more was considered to be good.-The factors that induced poor adherence to treatment.Given that the Ethic Committee was not available at the period of the study, the Ministry of the Health authorized the survey.The median % of medication doses taken by treated groups were compared using ANOVA method : t test was used for the sex factor; Mann-Whitney Rank sum test was used for the ARVs procurement and the ARVs combination prescribed and Kruskal-Wallis one-way analysis of variance on ranks method was used for the age groups and the educational level. The difference between the groups was considered to be significant if p < 0.05.A total of 99 patients (77.3%) of 128 interviewed during the investigation, accepted to be submitted to the questionnaire.Of the total sample (n = 99), 76 were female (76.8%) and 23 male (23.2%) with a sex ratio of 0.3. The age of patients ranged between 21 to 57 years, with an average age of 36.8 years. The age group from 36 to 45 years was more representative (39.4%), followed by 26 to 35 years (34.3%).Among the patients included in this study, sixty one percent were under an individual financial participation of "5 000 fcfa" per month (approximately US $ 11 reduced to US $ 2 since November 2005), the remaining received ARVs free of charge.Forty four patients (44.4%), knew perfectly the names of various ARVs included in the combination regimens. All respondents had a perfect knowledge of the treatment schedule .All patients have received a combination of three ARVs. Four different ARVs combinations ) were legalized, of which one available fixed-dose combination (lamivudine + stavudine + nevirapine). Only 39.4% of patients have received this fixed-dose combination as against 60.6% who were placed on non-fixed-dose combinations.The treatment regimen containing 2 nucleoside reverse transcriptase inhibitors (NRTIs) + 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) was used in 89.9% of patients; While the remaining 10.1% were placed on 2 NRTIs + 1 protease inhibitor (PI) based regimens  patients (62.62%) reported 95% or more of the doses taken. Table Forgetting (34.9%), travel 25.6%), cost of treatment (13.9%) and side effects (11.6%) were the main factors of poor adherence reported by the 43 patients who missed at least once a dose intake  stopped or changed one or more ARVs included in the treatment regimens because of side effects in 6 patients (6.1%), inefficiency in 4 patients (4%) and because of disease in 2 patients (2%).The assessment of the adherence level by interviewing PLWHA seems to be an acceptable method in Africa. It is simple, cheap and accessible. This method has, however some limits . The fact that the investigator is unknown to the patients, that he is not a member of the health care team and the guarantee of patient's anonymity limit this bias (e.g. the patients were not afraid of being criticized for poor adherence). An additional objective method (e.g. a count of returned pills) would have helped to improve the estimation of adherence level.The enrollment of members of the association could lead to a biased selection if the survey acceptation is related to a certain profile of patients that we didn't clarified. However, this bias was limited because the enrollment concerned consecutive patients attending EVT health care centres during the period of the study.The sex ratio in the present study (0.3 with 76.8% of women) is twice as high compared to that observed by PNLS  and loweThe whole eligible patients followed the regimens and the treatment schedule prescribed compared to Diabate et al's report in Ivory Cost  . HoweverStandard triple-ARVs combination regimens were prescribed. Four types of ARVs combinations of which two were based on 2 NRTIs + 1 NNRTI (standard first-line regimen proposed by WHO) and two on 2 NRTIs + 1 PI  of patients were in 2 NRTIs + 1 NNRTI-based regimens  , but lowTable The existence of tools or methods to promote the adherence was also reported. In the present study, 43.4% (n = 43) of patients reported using at least one  compared to 27.9% who stated being reminded by parents.Forgetting, travel, cost of treatment and side effects Figure  have beeTravels were the second main factor of poor adherence. This factor of non-adherence reveals the problem of the lack of a pill container containing at least all daily doses.The cost of treatment comprising transport, food support and laboratory tests were cited as main obstacles to optimal adherence. Previous studies have reported the incidence of payment factor on the rate of loss in HIV-infected patients' follow-up and/or adherence in Kenya . The risSide effects were the 4th barrier of non adherence (11.6%). They were collected on the basis of patients' reports. As a result, we have not considered appropriate to mention them since they are not validated as such in contrast to the report of Bhengu et al  who condA total of 12 patients (12.1%) stopped or changed one or more ARVs of the combination regimen for side effects, inefficiency of treatment and for illness conditions compared to 49.9% reported in the national survey conducted by PNLS .Overall, a review of the literature shows that the ART-adherence determinants include institutional, socio-economical, psychological and therapeutic factors to take in account in the management of PLWHA care. However, the present study didn't observe any epidemiological characteristic associated with poor adherence (medication doses taken less than 95%). To reach optimal adherence level (100%), our findings suggest the improvement of PLWHA follow-up with the help of adherence data sheets, the counseling/information/education interventions concerning the virological, biological, therapeutic and public health risks of non-adherence to ARVs therapy.Our results have shown that the knowledge and the capacity for adherence to ARVs treatment of PLWHA in the present study are satisfactory but have not reached the optimum desirable level. However, these results reflect the quality of the association "Espoir Vie Togo" interventions toward PLWHA. They should encourage the association EVT and all actors involved in the fight against AIDS to maintain and strengthen counseling, education, training and information interventions for PLWHA with a view to overcoming the potential barriers of poor adherence, given that non-adherence leading to the development of ARVs-resistant HIV is a public health concern.AIDS: Acquired Immune Deficiency Syndrome; ART: Antiretroviral Therapy; ARVs: Antiretrovirals; ARVs-GF: Antiretrovirals supported by Global Fund; CAMEG-Togo: Centrale d'Achat de Médicaments Essentiels et Génériques; EVT: Espoir Vie Togo (Association); HIV/AIDS: Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome; HIV: Human Immunodeficiency Virus; NNRTIs: Non-Nucleoside Reverse Transcriptase Inhibitors; NRTIs: Nucleoside Reverse Transcriptase Inhibitors; PI: Protease Inhibitor; PLWHA: People Living with HIV/AIDS; PNLS-Togo: Programme National de Lutte contre le SIDA; WHO: Word Health Organization.The authors declare that they have no financial or no non-financial competing interests in relation to the present manuscript.YP conceived, designed and coordinated the study, he carried out statistical analysis and drafted the manuscript; KT participated in the design of the study and the questionnaire, he carried out the study (interviewing and data collection), used the data collected for sustaining a doctor thesis of pharmacy; AB, VPP and IPG contributed by means of their respective competence and their experiences to the manuscript reviewing critically for its intellectual content. All authors read and approved de final version of the manuscript; EKK facilitated the interview and offered some facilities to the interviewer.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6904/10/11/prepubQuestionnaire for assessing PLWHA's knowledge and adherence level to antiretroviral therapy. The questionnaire sought the epidemiological characteristics of PLWHA, their knowledge of ARVs treatment, their adherence level to ART, the factors of poor adherence, the side effects reported and the prescription of treatment.Click here for file


Scale up of paediatric antiretroviral therapy in resource limited settings continues despite limited access to routine laboratory monitoring. We documented the weight and height responses in HIV infected Ugandan children on highly active antiretroviral therapy and determined clinical factors associated with successful treatment outcomes.A prospective cohort of HIV infected children were initiated on HAART and followed for 48 weeks. Body mass index for age z scores(BAZ), weight and height-for-age z scores (WAZ & HAZ) were calculated: CD4 cell % and HIV-1 RNA were measured at baseline and every 12 weeks. Treatment outcomes were classified according to; both virological and immunological success (VS/IS), virological failure and immunological success (VF/IS). virological success and immunological failure (VS/IF) and both virological and immunological failure (VF/IF).From March 2004 until May 2006, 124 HIV infected children were initiated on HAART. The median age (IQR) was 5.0 years (2.1 - 7.0) and 49% (61/124) were female. The median [95% confidence interval (CI)] BAZ, WAZ and HAZ at baseline were 0.29 , -1.2  and -2.06  respectively. Baseline median CD4 cell % and log10 HIV-1 RNA were; 11.8% (7.5-18.0) and 5.6 (5.2-5.8) copies/ml. By 48 weeks, mean WAZ and HAZ in the VF/IS group, which was younger, increased from - 0.98 (SD 1.7) to + 1.22 (SD 1.2) and from -1.99 (1.7) to + 0.76 (2.4) respectively. Mean increase in WAZ and HAZ in the VS/IF group, an older group was modest, from -1.84 (1.3) to - 0.41 (1.2) and -2.25 (1.2) to -1.16 (1.3) respectively. Baseline CD4 cell % [OR 6.97 95% CI (2.6 -18.6)], age [OR 4.6 95% CI (1.14 -19.1)] and WHO clinical stage [OR 3.5 95%CI (1.05 -12.7)] were associated with successful treatment outcome.HIV infected Ugandan children demonstrated a robust increase in height and weight z scores during the first 48 weeks of HAART, including those who failed to completely suppress virus. Older children initiating HAART with severe immune suppression were less likely to achieve a successful treatment outcome. These data emphasize the importance of initiating HAART early to ensure adequate immune and growth responses. Growth failure is a well recognized complication of HIV infection in children which can present as stunting, weight loss, failure to thrive and severe acute malnutrition which respond poorly to nutritional rehabilitation -3. The mHAART has become more widely available for children from resource-limited settings. The monitoring of antiretroviral treatment response in children and adults from sub-Saharan Africa remains mainly clinical with limited access to immunological and virological tests, except in the larger cities . TherefoThe study design and methods for this cohort of HIV infected children initiating HAART in Makerere University-Johns Hopkins University Collaboration (MU-JHU Care Ltd) HIV Care Clinic are reported elsewhere . In summA total of 130 HIV-infected children who were eligible for antiretroviral therapy (ART) were enrolled into the ART program at Makerere University-Johns Hopkins University Research Collaboration (MU-JHU) Kampala, Uganda. HIV infected children between 6 months and 12 years of age were initiated on HAART using the 2003 WHO criteria for antiretroviral therapy in resource-limited settings . For thiAll the children received a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based adult fixed dose combination (FDC) antiretroviral drug Triomune , containing stavudine (d4T 30 or 40 mg), lamivudine (3TC 150 mg) and nevirapine (NVP 200 mg). Those children who weighed less than 10 kg at HAART initiation, were prescribed syrup formulations of the same antiretroviral drugs until they weighed > 10 kg, when they were switched to Triomune. The triomune tablet was dosed based on the weight of the child and the individual antiretroviral (ARV) dosage was estimated according to weight band dosing . TherefoStudy visits were conducted at baseline and every week for the first month, every two weeks for the second month and then every four weeks until 48 weeks. At the routine follow-up visits, anthropometric measurements were recorded, a physical exam was performed as was clinical staging, based on the 2003 WHO staging for infants and children. At baseline and every 12 weeks, blood was collected for CD4 cell counts/percents and plasma HIV-1 RNA. Children also received follow up clinical care which included multivitamins, cotrimoxazole prophylaxis, and free medication for all acute illnesses. Caregivers and children, if age appropriate, received adherence counseling at each scheduled follow-up visit. Adherence monitoring was conducted at each follow-up visit and was based on pill counts and self-reports from caregivers. Caregivers were provided with a 30 day supply of the antiretroviral medication.2). Median weight-for-age z score (WAZ), median height-for-age z score (HAZ) and body mass index-for-age z score (BAZ) were calculated using the WHO-child growth standards [Heights and weights were recorded for each child at each routine follow-up visit. This was done by staff trained in carrying out accurate measurements; and standardized stadiometers and scales were used. The body mass index (BMI) was calculated from height and weight measures as defined by BMI equal to weight (kilograms)/height (metertandards . A z scoParticipants had blood drawn at baseline for measurement of complete blood cell count (CBC), CD4 cell count/percent, liver transaminases, renal function tests (creatinine) and plasma HIV-1 RNA. Repeat CD4 cell counts/percents and plasma HIV-1 RNA levels were done at 12, 24, 36 and 48 weeks after HAART initiation. All laboratory tests were performed at the MU-JHU Core Lab, Kampala Uganda, which is certified by the College of American Pathologists. The CD4 cell counts/percents were assessed by BD FACS Calibur instrument . Plasma HIV RNA levels were measured using the Amplicor HIV-1 Monitor Test, version 1.5 Standard assay . Plasma HIV-1 RNA levels >750,000 copies/ml were diluted and further assessed by dilution.Virological treatment success (VS) was defined as undetectable viral load (< 400 copies/ml) after 24 weeks of HAART and sustained through 48 weeks of follow up. Immunological treatment success (IS) was defined as achievement of a CD4 cell percent above the age cut off level for severe immunosuppression  after 24 weeks of HAART and sustained throughout the follow up period.Laboratory based Definitions of Treatment Success used in this analyses: HIV-1 RNA levels that were <400 copies/ml were considered undetectable and a successful treatment outcome for the purpose of these analyses. Descriptive statistics are presented as medians with inter-quartile ranges (IQR) and means with standard deviations (SD). Proportions of different baseline characteristics of study children and their respective 95% confidence intervals (CIs) are also provided. Chi square test p-values were used to compare baseline categorical variables. Kruskal Wallis p-values were used to compare medians of continuous variables at baseline. The primary endpoint for this analysis was achievement of a viral load less than 400 copies/ml at 24 weeks sustained through to 48 weeks, and achievement of CD4 cell count/percent above level of immune suppression for age. The children were classified into treatment outcome groups: virological and immunological success (VS/IS), virological success and immunological failure (VS/IF), virological failure and immunological success (VF/IS) and both virological and immunological failure (VF/IF). Mean WAZ and HAZ scores at the different time points of follow up after HAART initiation were compared using ANOVA and Scheffe's multiple comparison test. Factors associated with treatment success were analyzed using multinomial logistic regression and presented as univariate and multivariate analyses. In order to establish whether growth in children predicts virological and immunological treatment outcome after 48 weeks of HAART we conducted a logistic regression model for the different baseline z-scores and slope in the first 24 weeks. In this model, we categorized virological and immunological outcome as 1  and the other treatment outcome groups as 0. The utility of the WAZ, HAZ or growth velocity as predictors of successful treatment outcome was determined by calculating the sensitivity, specificity and ROC curves. Generalized estimating equations (GEE) were used to analyze weight and height velocity for different age groups during the 48 weeks of follow-up adjusting for various baseline factors. All statistical analyses were assessed for statistical significance at the p < 0.05 alpha level. All statistical analyses were performed using STATA Version10 .The baseline characteristics of the 124 HIV infected children enrolled into the study and initiated on HAART are presented in Table Mean changes in WAZ and HAZ scores during the 48 weeks of HAART therapy by treatment outcome groups are presented in Figure The VS/IS and VF/IS groups both had significant improvements in mean HAZ and WAZ scores on therapy, suggesting that complete viral suppression is not a requirement for an initial increase in weight and height Figure . The VF/When the treatment outcome groups were categorized by age, the VS/IF and VF/IF groups did not include any children less than one year of age, indicating than none of the infants had experienced immunological failure by 48 weeks on HAART Figure , 4. All When the baseline characteristics were placed into a univariate model for association with the successful treatment outcome group (VS/IS) compared to the other treatment outcome groups combined, only CD4 cell % at baseline was significantly associated with successful treatment outcome Table . Weight In a multinomial logistic regression, older age >18 months (p < 0.001), lower (<10%) baseline CD4 cell % (p = 0.001) and lower (<-2 SD) baseline HAZ (p < 0.001) were significantly associated with immunological failure alone (VS/IF), while lower age < 18 months (p = 0.027) was associated with virological failure alone (VF/IS); and lower CD4 cell % (p = 0.014) was associated with an observation of a both a virological and immunological failure(VF/IF) at 48 weeks. Age had the greatest predictive probability (44%) for observing both an immunologic and virologic success.Eighty six percent (107/124) of the children had undetectable viral load (< 400 copies/ml) and 73% (90/124) had immune restoration after 48 weeks of HAART. The proportion of children less than one year, one to three years and over three years of age with VS at 48 weeks were 50% (3/6), 82% (34/38) and 90% (68/73) respectively. The proportion of children with immunological success (IS) in the same age groups were 83% (5/6), 97% (37/38) and 89% (65/73) respectively. The one child under one year of age (1/6) who did not achieve immunological success at 48 weeks had a CD4 cell percent of 24%. The mean CD4 cell percent after 48 weeks of HAART was significantly different for the 4 categories: 32.4% (SD 7.0) in the VS/IS, 18% (SD 4.9) in the VS/IF, 32.2% (SD 4.9) in the VF/IS, 17.5% (SD 4.5) in the VF/IF group (p < 0.001). Twenty four weeks after HAART initiation, the mean log10 HIV RNA in the VS/IS, VS/IF, VF/IS and VF/IF was also different: 2.6 (SD 0.37), 2.7 (SD 0.13), 4.0 (SD 0.80) and 4.8 (SD 0.79) respectively (p < 0.01). By definition, all the children in the VS/IS and VS/IF groups had HIV-1 RNA < 400 copies/ml at 24, 36 and 48 weeks on HAART; none of the children in the VF/IS and VF/IF groups had a viral load < 400 copies/ml at the same time points.Used by themselves, the baseline WAZ, HAZ and 24 week WAZ and HAZ, and first 24 week WAZ and HAZ velocity showed modest to low sensitivity (< 63%) and specificity (< 42%) (data not shown) for predicting successful treatment outcome. However, when they were used together in a model to predict success or failure at a cut-off of model probability >0.5, there was increased sensitivity of 87.3%, but very low specificity of 27.0%.Similar to other studies from Africa and other resource limited settings, HIV infected children in this study experienced a significant increase in height and weight after initiation of NNRTI based HAART -24. The Older infected children in resource limited settings are usually long term survivors with severe immunosuppression and are less likely to have a rapid increase in height on HAART . In our The children who initiated HAART with a low CD4 cell percent, regardless of age were less likely to have a robust increase in CD4 cells. It seems these children, in fact have lost their potential for 'good enough' immunological reconstitution and therefore they do not reach our threshold for 'immunological success' within the first 48 weeks on therapy. These findings are consistent with other studies where delay in initiation of HAART is more likely to lead to treatment failure in children and adults ,20,28. OOur documentation of early growth responses on HAART, despite inadequate viral suppression in children from a resource limited setting is encouraging. However, the continued replication of virus on HAART leads to selection of resistant mutations which may limit future treatment options ,31,32. CThere were certain limitations to our study including the small number of children in the failure groups and the lack of growth data for HIV negative control children which may have affected the results. Also, the follow-up duration was 48 weeks so we were unable to assess the long term impact of HAART on growth, despite inadequate viral suppression. However, the strength of this study is that it was a prospective cohort with longitudinal clinical and laboratory data collected consistently with no child lost to follow up, except for those who died. In addition, the children had high adherence levels to HAART and the majority experienced viral and immune treatment success with associated improvement in growth. Larger studies with longer follow up on therapy would be beneficial in documenting the sustained growth response of infected children and guiding future treatment strategies for children from resource limited settings.In a cohort of HIV infected Uganda children we demonstrated a significant increase in weight and height during treatment with HAART. The age at initiation of HAART determined the magnitude of the growth response with the more significant increases in weight and height response documented in the youngest age group (<1 year). Of note, those children who did not experience complete viral suppression on therapy but did show immunologic success also showed a marked improvement in growth parameters. Children who initiated therapy with severe immune suppression were less likely to restore immune function and only had modest growth response. These data emphasize the importance of initiating HAART early to ensure adequate immune and growth responses.The authors declare that they have no competing interests.PMM corresponding author, contributed to the study design and conduct, analysis and writing of the manuscript. All authors read and approved the manuscript and agreed to the submission.PM contributed to the statistical analysis and writing of the manuscript, LBM contributed to the conduct of the study (study coordinator), collection of data, analysis and writing of the manuscript, PA contributed to collection of data and analysis, DB (senior statistician) contributed to study design, statistical analysis, data interpretation and writing of the manuscript, MM contributed to the statistical analysis and interpretation, TT contributed to the analysis, review and writing of the manuscript. MGF contributed to the writing and review of manuscript. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/10/56/prepub


Simultaneous control of blood glucose and other risk factors such as hypertension and dyslipidaemia is essential for reducing the risk of complications associated with type 2 diabetes mellitus (T2DM). As relatively few patients with T2DM have their risk factors managed to within the limits recommended by the American Diabetes Association, American College of Endocrinology or National Cholesterol Education Program Adult Treatment Panel III guidelines, treatment that can simultaneously control more than one risk factor is of therapeutic benefit. Clinical studies have shown that bile acid sequestrants have glucose-lowering effects in addition to their low-density lipoprotein cholesterol-lowering effects in patients with T2DM. The bile acid sequestrant colesevelam hydrochloride is approved as an adjunct to antidiabetes therapy for improving glycaemic control in adults with T2DM. This review examines data from three phase III clinical trials that evaluated the glucose- and lipid-lowering effects of colesevelam when added to the existing antidiabetes treatment regimen of patients with T2DM. Heart disease and stroke are the leading cause of mortality in patients with diabetes, accounting for approximately 65% of deaths in this group ,2. The hEpidemiological evidence suggests that the presence of microvascular complications [predicted by glycosylated haemoglobin (HbA1c) levels] may increase the risk of developing macrovascular complications in patients with T2DM –7. AlthoBile acid sequestrants are well-established therapies for the treatment of hyperlipidaemia, and therapy with cholestyramine has been shown to contribute to reductions in both the progression of coronary heart disease and in the risk of CVD events ,17. CompClinical evidence has suggested that bile acid sequestrants could also improve glycaemic control in patients with T2DM –28, and The addition of colesevelam to established antidiabetes monotherapy or combination therapy with metformin, sulfonylureas or insulin in patients with T2DM was evaluated in three randomized, double-blind, placebo-controlled clinical trials –28. The When added to established metformin therapy, colesevelam resulted in further reductions in HbA1c at week 6 . By the end of the trial at week 26, the mean treatment difference (placebo-corrected change from baseline) in HbA1c was −0.54%  . In addiA prespecified subgroup analysis investigated the effects of colesevelam when added to metformin monotherapy or metformin combination antidiabetes therapy. At week 26, the addition of colesevelam to metformin monotherapy resulted in a mean treatment difference in HbA1c of −0.47%  while the addition of colesevelam to metformin in combination with other antidiabetes therapy resulted in a mean treatment difference in HbA1c of −0.62%  . In thisThe addition of colesevelam to metformin therapy resulted in a significant reduction in LDL-C of approximately 16% (p < 0.001) at week 26 ; table 3The effect of colesevelam on non-HDL-C levels is interesting given that non-HDL-C is considered a secondary target of lipid-lowering therapy in patients with T2DM with triglyceride levels ≥200 mg/dl (≥2.3 mmol/l) . Non-HDLThere were improvements with colesevelam in the lipoprotein ratios that are most predictive of CVD risk ,32. ThesPatients treated with colesevelam exhibited a moderate, but non-significant increase in triglyceride levels compared with placebo  ; table 3The addition of colesevelam to established sulfonylurea monotherapy or combination therapy resulted in a further reduction in HbA1c, with an overall mean treatment difference of −0.54%  after 26 weeks . A signiColesevelam resulted in a significant mean treatment difference from baseline in LDL-C at week 26  ; table 3The addition of colesevelam to stable insulin only therapy or insulin therapy in combination with oral antidiabetes agents resulted in an additional reduction in HbA1c   after 16At week 16, colesevelam significantly reduced LDL-C levels as evidenced by a mean treatment difference of −12.8% (p < 0.001). Although the addition of colesevelam to insulin therapy also resulted in reductions from baseline in total cholesterol, non-HDL-C, and HDL-C at week 16 ; table 3The addition of colesevelam resulted in a consistent reduction in HbA1c [ranging from 0.50–0.54% (−29.0 to −29.4 mmol/mol)] across all three trials, regardless of the background antidiabetes medication used, that was accompanied by reductions in fasting plasma glucose. Furthermore, colesevelam treatment resulted in a greater percentage of patients achieving either a reduction in HbA1c ≥0.7% (≥15.8 mmol/mol) and/or fasting plasma glucose ≥30 mg/dl (1.7 mmol/l) at study endpoint compared with placebo. Colesevelam also reduced LDL-C and non-HDL-C levels when added to ongoing antidiabetes therapies, regardless of whether subjects were on ongoing monotherapy or combination therapy regimens. Colesevelam increased triglyceride levels; however, these increases were accompanied by reduced LDL-C, total cholesterol, and non-HDL-C levels, and increased HDL-C and in the lipoprotein ratios that typically denote increased cardiovascular risk. These results highlight the dual ability of colesevelam to improve both HbA1c and LDL-C in patients with T2DM.Safety is an important issue in patients with T2DM who are often taking multiple medications to address the overall pathology of insulin resistance. Colesevelam, unlike most new pharmacological agents, has an established safety record and was generally well tolerated across all three trials in patients with T2DM. The rate of adverse events (AEs) was similar between the colesevelam and placebo groups, and most AEs were considered unrelated to the study medication . GastroiThe risk of hypoglycaemia is an important consideration for any antidiabetes agent. In these three trials, colesevelam did not significantly increase the risk of hypoglycaemia when added to existing metformin-, sulfonylurea- or insulin-based therapy in patients with T2DM. In the metformin trial, one patient who received colesevelam experienced a mild episode of hypoglycaemia . In the Mean changes in safety laboratory parameters and vital signs were similar in the treatment groups of each trial –28. OverColesevelam can increase triglyceride levels in patients with T2DM. Caution is therefore recommended in patients with triglyceride levels >300 mg/dl (>3.4 mmol/l), and colesevelam is contraindicated in patients with triglyceride levels >500 mg/dl (>5.7 mmol/l) and in patients with a history of hypertriglyceridaemia-induced pancreatitis . ColesevThe results of these trials are similar to those seen following the addition of thiazolidinediones to metformin or sulfonylurea therapy . FactorsThe mechanism(s) by which colesevelam lowers glucose levels in patients with T2DM is not yet clearly understood. However, there is increasing evidence that the glycaemic effects of bile acid sequestrants may occur through farnesoid X receptor (FXR/bile acid receptor), liver X receptor, fibroblast growth factor-19 and TGR5-mediated effects on intestinal glucose absorption and/or hepatic glucose metabolism, in addition to influences on peripheral insulin sensitivity, incretin effects and energy homeostasis. Bile acid activation of FXR has been shown to reduce expression of genes involved in gluconeogenesis including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. In addition, FXR may modulate hepatic glucose production during fasting and postprandial hepatic glucose utilization –40. AlteThe additional reduction in HbA1c and LDL-C levels achieved with the addition of colesevelam to current antidiabetes therapies may help patients with T2DM achieve target levels for HbA1c and LDL-C. Favourable modification of these two factors plus lowering non-HDL-C levels may make colesevelam a useful adjunctive therapy to reduce overall cardiovascular risk in patients with T2DM. Colesevelam is currently recommended for the treatment of T2DM in combination with antidiabetes therapies such as metformin, sulfonylurea and insulin, and has been added to the treatment roadmap developed by the American Association of Clinical Endocrinologists , and to


The aim of this study was to estimate the proportion of spontaneous viral clearance (SVC) after symptomatic acute hepatitis C and to evaluate the efficacy of 12 weeks of pegylated interferon alfa-2a in patients who did not clear the virus spontaneously.Patients with symptomatic acute hepatitis C were recruited from two “fever hospitals” in Cairo, Egypt. Patients still viremic three months after the onset of symptoms were considered for treatment with 12 weeks of pegylated interferon alfa-2a (180 µg/week).Between May 2002 and February 2006, 2243 adult patients with acute hepatitis were enrolled in the study. The SVC rate among 117 patients with acute hepatitis C was 33.8% (95%CI [25.9%–43.2%]) at three months and 41.5% (95%CI [33.0%–51.2%]) at six months. The sustained virological response (SVR) rate among the 17 patients who started treatment 4–6 months after onset of symptoms was 15/17 = 88.2% (95%CI [63.6%–98.5%]).Spontaneous viral clearance was high (41.5% six months after the onset of symptoms) in this population with symptomatic acute hepatitis C. Allowing time for spontaneous clearance should be considered before treatment is initiated for symptomatic acute hepatitis C. Management of acute hepatitis C is a complex issue. While studies have shown that treatment during the acute phase can achieve high (72%–98%) success rates In Egypt, the epidemiological situation differs from that of Western countries. HCV prevalence is very high  Among these patients, waiting for spontaneous clearance and treating only those still viremic three months after the onset of symptoms makes sense for two reasons: the higher rate of spontaneous clearance expected from patients with symptomatic compared to asymptomatic forms of acute hepatitis C ; and the cost savings incurred by not treating all patients, an important consideration in countries with limited resources, including Egypt. In this paper, we present the results of the follow-up of 117 patients diagnosed with symptomatic acute hepatitis C in Cairo. Patients who failed to clear the virus three months after the onset of symptoms were considered for treatment with 12 weeks of pegylated interferon alfa-2a.The recruitment of patients with symptomatic acute hepatitis C has already been described in our previous report of a pilot study performed in 2002 in Cairo All patients were interviewed by trained medical doctors, using a questionnaire on socio-demographic characteristics and risk factors for HCV infection in the past six months. Risk factors were categorized as high risk and low risk exposures based on the magnitude of the associations with HCV transmission documented in previous studies A 10 ml venous blood sample was collected for liver functions , and exclusion of acute hepatitis A and B by serological analysis . In patients with non-A non-B hepatitis, anti-HCV antibodies were assessed serologically , and HCV RNA Extraction was performed using QIAmp Viral RNA Kit  according to manufacturer's recommendations. The Reverse Transcription and Polymerase Chain Reaction (RT-PCR) was done according to Abdel-Hamid et al, 1997 In patients with positive HCV antibodies and RNA, exacerbation of chronic hepatitis C by other infectious agents was ruled out using reverse transcriptase PCR for HEV-RNA (in house assay using ORF1 and ORF2 primers) and serological testing . All tests were performed at the Viral Reference Hepatology Laboratory (VHRL).1) Definite acute hepatitis C if negative anti-HCV antibody and positive HCV RNA; 2) Probable acute hepatitis C if positive anti-HCV antibody and HCV RNA associated with ALT≥10 times the ULN, history of high risk exposure 1 to 3 months prior to diagnosis, negative serology/PCR (see above) for other infectious agents , no history of drugs or pesticides exposure, and no other cause of hepatitis .The diagnosis of acute hepatitis C was based on epidemiological findings, clinical examination, and laboratory test results. Accordingly, patients were categorized as All patients with acute hepatitis C were offered follow-up at the National Hepatology and Tropical Medicine Research Institute (NHTMRI) in Cairo. Visits were scheduled for clinical and biochemical assessment at 2, 3, 6, 12, 18 and 24 months, calculated from onset of symptoms. Antiviral treatment was not offered immediately in order to allow for spontaneous clearance of the virus; however, non-specific symptomatic treatment, such as antiemetics for nausea and vomiting, antipyretics for fever and analgesics for headache, were offered to all patients. Patients who were still HCV RNA positive three months after the onset of symptoms were screened for treatment eligibility. Exclusion criteria for treatment were age <18 years or >65 years; poorly controlled diabetes; thyroid disease ; autoimmune diseases; alcoholism; liver cirrhosis; hepatocellular carcinoma; psychiatric disease such as history of severe depression, psychosis, suicidal ideas; epilepsy; non-stabilized medical or surgical condition; hemoglobin<11 g/dl, leucocytes <3000/µL, polynuclear neutrophils <1500/µL, platelets <100 000/µL, and blood creatinin >150 µmol/L. For females: pregnancy or breastfeeding were contra-indications (an effective contraception was requested during the treatment period).Treatment with free pegylated interferon [PEG-IFNα-2a ] (180 µg/week) for 12 weeks was started 4–6 months after onset of symptoms in those still positive at that date, provided there were no contraindications. Injections were provided at the NHTMRI clinic under medical supervision. In patients still HCV RNA positive after 12 weeks of treatment, treatment was extended for another 12 weeks. Patients were seen weekly during the treatment period, and every six weeks afterwards until week 36 (end of follow-up for those treated for 12 weeks), or week 48 (end of follow-up for those treated for 24 weeks). The dosage of PEG-IFN α-2a was reduced for two weeks to 90 µg/week if neutrophil or platelet counts fell below 750/µL and 50,000/µL, respectively. After the 2 weeks, dose was raised back to 180 µg/week if neutrophil and platelet counts went above 750/µL and 50,000/µL, respectively. Treatment was discontinued if neutrophil or platelet counts fell below 500/µL and 25000/µL, respectively, or when serum hemoglobin concentrations decreased below 8.5 g/dL. Doctors' judgment was the basis for dose reduction and discontinuation of PEG-IFN α-2a if other commonly reported adverse events  were reported. The primary endpoint was sustained virological response (SVR), defined as negative serum HCV RNA 24 weeks after the end of treatment. Secondary endpoints were the absence of detectable levels of serum HCV RNA at the end of treatment and the normalization of ALT levels. Viral load was determined using the Cobas Amplicor HCV Monitor test, v 2.0 (Roche Diagnostic Systems).All patients with acute hepatitis consulting or hospitalized in the two participating hospitals were included in the study after providing a written informed consent. A separate informed consent was required for the patients who were treated with pegylated interferon. The entire study protocol has obtained clearance from the Ministry of Health and Population in Egypt, and the Institutional Review Board for Human Subject Research at NHTMRI. The 12-week pegylated interferon trial protocol for patients with acute hepatitis C has been registered under the following number: NCT00158522 (ANRS1213).Spontaneous viral clearance (SVC) was defined as no HCV RNA in serum, in the absence of treatment, for two consecutive HCV PCR tests during follow-up. Patients treated with pegylated interferon were censored at the time of treatment initiation. Date of clearance was chosen as the midpoint between the last positive PCR and the first negative PCR defining clearance. The SVC rate was estimated using Kaplan-Meier estimates, with time 0 equivalent to onset of symptoms. A Cox proportional hazards model was used to identify factors associated with SVC. Factors with p values less than 0.25 in univariate analysis were tested in the multivariate model, and p values less than 0.05 were considered significant. Statistical analyses were performed using Stata 8 statistical software .Between May 2002 and February 2006, 2243 consecutive adult patients with acute hepatitis were recruited from Abbassia and Imbaba Fever Hospitals. Of these, 647 (28.8%) were diagnosed with acute hepatitis A, 609 (27.2%) were diagnosed with acute hepatitis B, and 401 (17.9%) tested positive for HCV RNA by PCR. Of the patients positive for HCV RNA, those with negative HCV antibodies  were considered as definite acute hepatitis C. Of the 322 with positive HCV antibodies, 114 had ALT levels lower than 10 times ULN, and were therefore no longer considered potential acute hepatitis C cases. Full assessment to determine final status  of the 160 patients with acute hepatitis C. In total, 51 patients spontaneously cleared the virus, with the following Kaplan-Meier estimates (95% CI) at specific points during the follow-up period: 33.8% (25.9%–43.2%) at 3 months, 41.5% (33.0%–51.2%) at 6 months, 44.0% (35.2%–53.9%) at 12 months, 45.5% (36.5%–55.6%) at 18 months, and 47.3% (38.0%–57.6%) at 24 months . For thoFrom the 77 patients still HCV RNA positive three months after the onset of symptoms, 17 were treated with pegylated interferon. Sixty patients were not treated for the following reasons: 16 had negative HCV RNA by PCR during the screening period (7 who definitely cleared the virus and 9 who turned positive again during follow-up), 14 had medical contra-indications to treatment, 20 did not show up at the pre-treatment screening visit but re-appeared at subsequent follow-up visits more than six months after the onset of symptoms, 6 were definitely lost to follow-up, and 4 refused treatment. Seventeen patients started treatment with pegylated interferon. Their baseline characteristics are summarized in Between May 2002 and February 2006, approximately 7% of adult patients presenting with acute hepatitis in two hospitals of Cairo had acute hepatitis C. In absolute numbers, around 3 cases per month were diagnosed in these two hospitals during the study period. This figure contrasts with the rarity of acute hepatitis C diagnoses in Western countries. Most patients had recent exposure to invasive medical procedures, half of which were surgical cases, suggesting the need for strict preventive measures to control this source of infection.In the ensuing cohort of 117 patients with symptomatic acute hepatitis C, 41% had spontaneously cleared the virus six months after onset of symptoms. This figure, found in a patient group infected primarily with HCV genotype 4, is similar to the 41% estimate obtained from a cohort of patients with symptomatic community-acquired acute hepatitis C in Italy whose infecting genotypes were: 1 (42%), 2 (20%), 3 (16%), 4 (2%), and unknown (20%) One of the crucial issues in acute hepatitis C management is when to treat. While randomized trials comparing different timing of treatment initiation may be the most rigorous approach to the issue, more than 200 patients in each arm would be required to have 80% power to show a 10% difference  between two strategies. Such sample sizes will be difficult to achieve for a rare disease like acute hepatitis C. Descriptive studies like this one may therefore be useful in making educated guesses for patient management until the results of randomized trials are available. In this study of symptomatic acute hepatitis C, 80% of all SVC took place within three months after onset of symptoms (or five months after infection taking into account the two months average duration between infection and symptoms). Thus, waiting for three months after onset of symptoms to treat may be necessary in symptomatic acute hepatitis C to allow SVC to take place. The question arises of whether waiting so long after infection to provide treatment might compromise the response of the patients who will ultimately need it. A study in which treatment with interferon was initiated one year after the onset of symptoms achieved a disappointing 40% SVR rate In conclusion, this study has documented the high spontaneous clearance rate of symptomatic acute hepatitis C, and shown that 80% of SVC had taken place three months after onset of symptoms. In patients who had not spontaneously cleared the virus by that time, SVR could be obtained in 88.2% with a short 12-week monotherapy with pegylated interferon alfa-2a.


On World AIDS Day 2009, it is appropriate that we reflect on the accomplishments in HIV therapy that have been made over the past decade. First, we should recognize that the impact of the XIIIth International Conference on AIDS in Durban, South Africa, in 2000 was much more than scientific. It also highlighted the non-acceptability of continuing to deny access to life-saving antiretroviral drugs to HIV-infected people in developing countries. This was in spite of efforts by then President Thabo Mbeki of South Africa to undermine the conference through his ridiculous and irresponsible insinuations that HIV might not be the cause of AIDS. Since 2000, it is estimated that the numbers of people in Africa receiving antiretroviral therapy has increased to approximately four million from about 7000 at the time of the Durban Conference. However, the fact is that almost all HIV-infected persons in developing country settings are today receiving therapies that are considered to be sub-standard by Western criteria.For example, the triple drug combination that is the most widely prescribed in the world, is termed Triomune. The reason it is so widely used is that it is cheap as well as generically produced, and is therefore extensively used in developing countries where the burden of HIV disease is so extensive. Triomune is a single pill that is taken twice daily. It includes three individual drugs that are termed stavudine (d4T), lamivudine (3TC), and nevirapine (NVP). Of these, it is only 3TC that continues to be widely used by patients in Western countries. Indeed, we have known for at least 7 years that the stavudine component of the Triomune regimen is associated with severe toxicities that can cause facial and body disfiguration . As a reThe problem gets worse. There is now substantial evidence to indicate that patients infected by the subtype C variants of HIV-1 that are predominant in sub-Saharan Africa may be especially prone to develop certain drug resistance-associated mutations in the event that they fail their antiretroviral therapy ,3. One oFortunately, the World Health Organization has recently recommended that TDF be substituted, wherever possible, for stavudine in the context of initial therapeutic regimens in developing countries. However, it may take years for poorer countries to be able to access alternate medicines such as TDF, which costs at least twice as much as stavudine, even if it is generically produced. In all likelihood as well, generic manufacturers of Triomune, that have stockpiled huge amounts of this antiquated triple cocktail formulation, will be unhappy if their amassed drug supplies do not make their way to market.Another major issue in regard to the clinical management of HIV-infected individuals in developing countries involves the performance of PCR-based tests to monitor levels of viral RNA in plasma. It has long been argued by some that this test is expensive and that the money involved in performing clinical monitoring of plasma viremia might be better spent on providing access to drugs. However, it is important to understand that the monitoring of plasma viremia represents an essential component of HIV clinical management in all Western countries and provides key information in regard to whether a drug regimen is working or not. Indeed, it is considered to be unacceptable if a patient's viral load in plasma cannot be brought down to and maintained below levels of dectability of the test, i.e. < 50 copies of viral RNA per ml of plasma.The reason that it is essential to offer plasma viremia testing is simple. Once HIV plasma viremia begins to rise, this is usually a sure indication that the therapeutic regimen being used has probably failed, most likely for reasons of HIV drug resistance as a consequence of drug-selected mutations within the target genes of HIV therapy i.e. reverse transcriptase, protease, and integrase.It is not only that these mutations can render antiretroviral drugs less useful than they might otherwise be but, in addition, because such mutations can sequentially accumulate if a patient continues to be treated with a drug that is being employed during treatment failure. This, in turn, can lead to higher levels of drug resistance that might otherwise occur as well as to the potential for sexual transmission of resistance-associated mutations.In certain instances, a more serious consequence may be that the accumulation of drug resistance mutations may prevent newer compounds that represent a next generation of drug development from being effective. For example, the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (ETV) is an excellent compound that maintains efficacy against viruses that contain the most common mutations associated with resistance against two first-generation NNRTIs, NVP and efavarenz (EFV). However, if patients remain on either of these drugs once the most common of these mutations, i.e. K103N, has appeared, they will be likely to develop a wide array of other NNRTI-associated mutations, that will compromise the use of ETV .The problem with monitoring patients by means other than plasma viremia, such as CD4 counts, is that the latter are not well-suited to provide an accurate assessment of the state of viral replication within infected individuals. Although CD4 monitoring is essential and provides vital information in regard to the status of the immune system, it is well known that drops in levels of CD4 counts usually take place long after plasma viremia has started to increase. As a consequence, patients who remain on non-effective triple drug regimens will continue to accumulate drug resistance-associated mutations during periods of relative CD4 stability, since it is only the long-term consequences of unchecked viral replication that lead to CD4 declines. While there is now a trend toward encouraging the use of viral load diagnostics in all developing country settings, this recommendation may have come too late for millions of individuals who have already accumulated multiple drug resistance mutations in their HIV genomes, thereby compromising future therapies.3 [3, often because they may then decide to seek medical advice after first developing AIDS-related symptoms.An additional major difference between therapeutic standards in Western vs developing countries involves the question of when to start therapy. There is now consensus in Western countries that patients ought to begin therapy when their CD4 counts are still above 350 cells/ml3 . AllowinEfforts are now being made in all Western settings to try to identify HIV-infected individuals far earlier than was previously the case for several reasons. Among these are the potential public health benefits of beginning antiretroviral therapy earlier, such that viral load will quickly diminish and infected individuals will be less likely to transmit virus to others . A seconIn contrast, most individuals in developing countries remain unlikely to be diagnosed with CD4 counts that are above 200. It will take monumental efforts to bring more widespread and efficacious testing for HIV to developing country settings in order that patients may benefit from HAART to the same extent as has occured in the West. This problem is also complicated by the fact that stigmatization of HIV disease is far worse in many developing countries than is the case, for example, in Western Europe and North America .As if the above were not enough, there is even concern that the generic drugs being made available in some developing countries may not be of the same quality as those that are produced by major pharmaceutical companies . It is vIn short, considerable progress has been made in developing settings, including most African countries, in regard to HIV drug access. However, enormous chasms in regard to standards of care, diagnostic services, and qualities of drugs employed continue to distinguish developing from developed countries, as has been previously pointed out . It is sMark A. Wainberg is Professor of Medicine and of Microbiology at McGill University in Montreal where he is the Director of the McGill AIDS Centre at the Jewish General Hospital. He was the President of the International AIDS Society between 1998-2000 with responsibility for organization of the XIIIth International Conference on AIDS that was held in Durban, South Africa during July 2000.


There is increasing evidence that metabolic adverse effects associated with antiretroviral therapy may translate into an increased cardiovascular risk in HIV-1-infected patients.To determine the prevalence of risk factors for cardiovascular disease (CVD) among HIV-1-infected persons, and to investigate any association between them, stage of HIV-1 disease, and use of antiretroviral therapies.Multicentric, cross-sectional analysis of CVD risk factors of treated patients in the VACH cohort. The data collected includes: demographic variables, cigarette smoking, diabetes mellitus, hypertension, dyslipidemia, body mass index, stage of HIV-1 infection, and antiretroviral therapy.The analysis included 2358 patients. More than 18% of the study population was at an age of appreciable risk of CVD. 1.7% had previous CVD and 59.2% were smokers. Increased prevalence of elevated total cholesterol was observed among subjects receiving an NNRTI but no PI , PI but no NNRTI , or NNRTI + PI  compared to patients treated only with nucleoside reverse transcriptase inhibitors (NRTI). Higher CD4 cell count, lower plasma HIV-1 RNA levels, clinical signs of lipodystrophy, longer exposure times to NNRTI and PI, and older age were all also associated with elevated cholesterol levels. The use of lipid lowering agents was very low among our patients.Patients in the VACH cohort present multiple known risk factors for CVD, and a very low rate of lipid lowering therapy use. NNRTI and/or PI-based antiretroviral therapies are associated with the worst lipid profile. This is more frequent in older subjects with greater CD4 counts and controlled HIV-1 replication. The widespread use of highly active antiretroviral therapy (HAART) has converted HIV-1 infection into a chronic manageable illness that needs lifelong therapy. However, HAART is associated with metabolic side effects including hypercholesterolemia, hypertriglyceridemia, insulin resistance and more rarely diabetes mellitus, and possibly arterial hypertension . HAART-atranslated into clinical events of cardiovascular disease on a population level has been examined by a number of studies including cohort studies from the French Hospital Database , the HOPTo assess the risk of treatment-associated cardiovascular risk factors, we performed a cross-sectional analysis of the HIV-1-infected patients included in the Spanish VACH Cohort. The objectives of the present analysis were to determine the proportion of patients with an increased risk profile for cardiovascular disease. Furthermore, we tried to identify factors associated with the increased risk profile. Addition ally, our research was focused on the management of dyslipidemia in our cohort.The study is a multi-centre, cross-sectional study of the prevalence and management of dyslipidemia and other established CHD/CVD risk factors in all HIV-1-infected subjects, aged 18 or above, treated with HAART, in routine clinical practice from the Spanish VACH cohort treatment centers. Characteristics of VACH Cohort have been described elsewhere .Male or female subjects aged 18 years or above at the time of enrollment with a documented HIV-1 infection, which attend VACH cohort outpatient HIV-1 treatment centers for routine, scheduled, clinical appointments, were eligible for this study.In order to be eligible, subjects must have been on at least three antiretroviral drugs, at the time of the study visit. Antiretroviral (ARV) naïve subjects or ARV experienced, but currently untreated subjects or those currently treated with NRTI bi- or mono therapy were not eligible for this study. However, for the purpose of the study, we included patients treated with 3 NRTIs. Subjects who were hospitalized or have a frank cognitive impairment such as delirium or dementia on enrolment were not eligible either. Informed consent was obtained from the patients at study entryIn the VACH Cohort, data are prospectively collected according to standardized criteria, and are electronically stored in the Aplicación de Control Hospitalario , an application specifically developed for the management of the cohort data. On enrolment, standardized data collection electronic forms were completed at the sites providing information from physical examination, patient interview and patient case notes, concerning family history of coronary heart disease, patients’ prior history of CVD and diabetes, cigarette smoking, blood pressure, therapy for diabetes mellitus, lipid-lowering and anti-hypertensive therapy, the presence of clinical signs of lipodystrophy and fasting serum lipid levels. Further, all cumulative data characterizing the patient’s underlying HIV-1 infection since inclusion in any of the individual cohorts were collected, including information on demography, antiretroviral therapy, CD4 cell counts and HIV-1 viral loads. Dates of diagnosis of all AIDS-defining diseases are recorded, using the 1993 clinical definition of AIDS from the Centers for Disease Control and Prevention .6 (cells/l) or assessed as a continuous variable (log2 transformed). Similarly, HIV-1 RNA was stratified in strata of: <  500, 501–10 000, 10 001–100 000, and > 100 000 copies/ml, and also assessed as a continuous variable (log10 transformed).CD4 cell count was stratified in strata of 100 x 10Four categories were predefined: (i) currently receiving only NRTI; (ii) currently receiving NNRTI and NRTI but not PI; (iii) currently receiving PI and NRTI but not NNRTI; or (iv) currently receiving PI, NNRTI and NRTI. Previous antiretroviral therapy exposure was modelled as cumulative time spent using each of the three drug classes.The grouping of the risk factors assessed was defined prior to the initiation of the analysis. CVD risk factors were assessed as dichotomous categorical variables, where the cut-off levels chosen were conservative estimates of ‘high risk’ based on levels used for risk scoring in the background population -19. Patiet al.  . In all antiretroviral therapy groups, higher HIV-1 viral load was associated with a decreased risk of elevated total cholesterol ; overall the adjusted OR was 0.77 (95%CI: 0.68-0.88), P <  0.001, per 1 log10 increase in HIV-1 RNA.The association of antiretroviral therapy with lipid levels is shown in Table 3 and 4). Overall, the adjusted risk of elevated triglycerides decreased with increasing HIV-1 RNA , and there was also a significant association with CD4 cell count .In a univariable logistic model for cumulative antiretroviral drug exposure time, the OR for elevated triglycerides was 1.05 , 1.02  and 1.06  per year of exposure to NRTI, NNRTI and PI, respectively, associations essentially unchanged in the multivariable model (Tables 4) in the multivariate logistic model. The associations of CD4 cell count and HIV-1 viral load were similar for the absolute value of HDL-cholesterol and for total cholesterol.None of the current regimens were associated with an increased risk of low HDL-cholesterol (Tables 3 and 4) which was explained by a strong correlation of hypertension with other factors .More than 20% of the study population had hypertension. In a univariable logistic model, regimens containing NNRTI, PI or both drug classes were associated with a non statistically different risk of being hypertensive . The adjusted multivariate increment of risk per year of exposure was 8% for NRTI (p=0.011), 10% for NNRTI (p=0.031) and 4% for PI (0.243) (Table 4).tial risk of diabetes (Tables ). Antiretroviral therapy was highly associated with the presence of clinical lipodystrophy, with the highest risk among patients receiving a regimen containing all three drug classes (Tables 3 and 4). When assessed as an explanatory variable, lipodystrophy was associated with the presence of several of the CVD risk factors discussed above (Table 5). In a multivariable model including the total study population, and adjusting for co-variables as listed in Table 5, the adjusted OR for the association of lipodystrophy with elevated total cholesterol was 0.90 , elevated triglycerides 1.36  and decreased HDL 1.19 . The presence of lipodystrophy was associated with an increased risk of hypertension and diabetes OR, 1.47  and 1.71 , respectively.In all regimen groups there were few obese patients  . However, only between a fourth and a fifth of those patients were currently receiving LLTIn the VACH population we have observed a high prevalence of multiple risk factors for CVD. VACH has the strength of having included more than 2000 treated patients with details concerning CVD risk factors, with an almost insignificant proportion of missing data. Similar to other studies , we founHowever, our findings have inherent limitations. Firstly, our findings are not applicable to other populations since the diversity of the study population, including women, minorities and means of acquiring HIV-1 infection, implies that the study may not be representative of the HIV-1-infected population in other industrialized countries. Furthermore, the Mediterranean basin is an area of low incidence in terms of coronary heart disease and its risk factors, which may make comparisons with similar studies difficult , 22. How1), which implies that the prevalence of the individual risk factors is precise.Other limitations are related to the observational design of the study. Firstly, the results presented are only associations from which no conclusions regarding causality can or should be drawn. Secondly, due to the observational design of the study, many measurements  are expected not to be always conducted in a uniform manner. However, international and national standardization of serum lipid measurements have been accomplished throughout the guidelines of the NCEP ATP II and the Spanish Society of Hypertension , 26. On Dyslipidemia was most strongly correlated with antiretroviral regimens currently being used, and less with a history of previous exposure to the different drug classes. This is consistent with previous reports, in which the PI-associated dyslipidemia occurred shortly after beginning therapy , 28 and The association between NNRTI-containing regimens and dyslipidemia has rarely been reported , althougWe found a strong association between elevated total cholesterol level and higher CD4 cell counts, which was present within each treatment category. Nevertheless, within each CD4 cell count stratum, the effect of antiretroviral therapy was clearly observed, which indicates that the effect of antiretroviral substances certainly cannot solely be explained by a reversal to ‘normal’ pre-disease cholesterol levels as a result of improved cellular immunity. The level of HDL-cholesterol, although to a lesser extent, likewise increased with more conserved cellular immunity, consistent with observations in the pre-HAART era . For totIn the VACH study, we have observed a high prevalence of other known and potential CVD risk factors among patients receiving either PI or NNRTI, including cigarette smoking, diabetes, hypertension and altered body composition. The overall prevalence of diabetes mellitus in the VACH study was 7.3%, similar to other studies that have shown an association between diabetes mellitus and use of PI , 27, 31,Recently, the issue of how young persons, with a low absolute risk may be at a substantially relative higher has been addressed in the European guidelines , and thiPere Domingo, Ignacio Suárez-Lozano, and Myriam Garrido were in charge of the design, coordination and wrote the article. Pompeyo Viciana, Fernando Lozano, Alberto Terron, MJosé Galindo, Juan Gonzalez, Pere Domingo, Esteban Ribera, Antonio Vergara, Ramón Teira, Paloma Geijo, Jaime Cosín, Bernardino Roca, Belen de la Fuente, Trinitario Sanchez, contributed to de design of the computer application, data entry for the study, local coordination and bring up ideas to complete the final version of the manuscript. Juan R Lacalle and Ferran Torres made the statistic analyses.This work was possible through an unrestricted grant from Bristol, Myers &; Squibb.


Selection of the K103N mutation is associated with moderately reduced in vitro fitness of HIV. Strains bearing K103N in vivo tend to persist, even in the absence of additional drug pressure, as minority quasispecies, often undetectable in genotyping resistance testing assays, performed at standard conditions. Here, we report on the rapid and long lasting selection of a K103N bearing strain as the dominant quasispecies after very short exposure to efavirenz in vivo.A 55-year-old Caucasian man was switched to efavirenz, zidovudine and lamivudine in February 2003, while on viral suppression in his first-line highly active anti-retroviral treatment regimen. One month later, he reported inconsistent adherence and his viremia level was 5700 c/mL. He did not attend further checkups until September 2005, when his viral load was 181,000 c/mL. The patient reported interrupting his medications approximately three weeks after simplification. The genotyping resistance testing assay was performed both on HIV RNA and HIV DNA from plasma, yielding an identical pattern with the isolate presence of the K103N mutation in the prevalent strain.Persistence of the K103N mutation as a majority quasispecies may ensue after a very short exposure to efavirenz. Our case would therefore suggest that the presence of the K103N mutation should always be ruled out by genotyping resistance testing assays, even after minimal exposures to efavirenz. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active anti-retroviral treatment (HAART) regimens are characterized by a good tolerance of relatively low levels of adherence to therapy, although resistance selection may ensue when adherence drops below the 75% threshold ,2. FirstA single dose of NVP administered during delivery in pregnant women to prevent mother from transmitting HIV to their babies was able to select K103N mutant strains, which could persist as minority quasispecies for as long as five years after drug exposure . Persist10, no GRT assay was performed at that time), pre-HAART CD4+ T-lymphocytes were 17/µL. After viral suppression, his CD4+ T-cell counts very slowly improved, approaching the 200/µL threshold only after 28 months of treatment. Therefore, his HAART scheme was not simplified, with no signs of drug-related toxicity ensuing. In February 2003, however, after approximately four years of treatment, the patient declared his intention to change his treatment drugs. According to the patient, he experienced treatment-related fatigue and had recent adherence failures. His viral load at that time, however, was still undetectable. His treatment was therefore switched to EFV, AZT and LMV.A 55-year-old Caucasian male patient infected with HIV for more than 10 years after heterosexual exposure, CDC class C since 1999 due to pneumocystis jiroveci pneumonia, was put on his first-line HAART regimen in November 1998, with indinavir, zidovudine (AZT) and lamivudine (LMV). His virological response was prompt and long lasting. Pre-HAART viremia level was 215,000 c/mL ; he reported inconsistent adherence. After that, he did not show up until March 2006. He was hospitalized due to clinical progression (high fever and remarkable weight loss), with a discharge diagnosis of disseminated atypical mycobacteriosis. On admission, CD4+ T-cell counts were 12/µL, and his viral load was 181.000 c/mL . The patient reported interruption of all his medications a few days after his last check in 2003, approximately three weeks after therapy simplification  and LMV 8 hours). Furthermore, chromatographic assays for EFV, performed seven days after the last dose, demonstrated sub-therapeutic concentrations of EFV in plasma (70-720 ng/mL) [ hours. F3) and pneumocystis jiroveci pneumonia. He never travelled abroad, and reported risky heterosexual behaviors up to some 10 years before presentation. As a consequence, although both the existence [He first presented in our ward in 2000, with very advanced HIV infection  or switched interruptions (replacement of the NNRTI with a boosted PI for a short period) of all drugs were less likely than those using simultaneous interruptions to have any NNRTI mutation in their GRT performed two months following the treatment interruption. They also demonstrated that patients who carried a NNRTI-mutation after the interruption achieved viral resuppression significantly less frequently than those who did not have any mutation in their resistance test .Our experience, although similar to that reported by Palmer et al. on one of their patients, would indicate that persistence of the K103N mutation as a majority quasispecies may ensue after a very short exposure to EFV, in the absence of wild type depletion, likely providing relative replicative advantage.Our case therefore suggests that the presence of the K103N mutation should be ruled out even after minimal exposures to EFV, reinforcing at the same time the need for a systematic evaluation of GRT in naïve patients and after any type of interruption of NNRTI-based HAART regimens, as well as the need for a wise strategy of NNRTI interruption.μL: microliter; EFV: efavirenz; GRT: genotypic antiretroviral resistance testing; HAART: highly active antiretroviral therapy; mL: milliliter; ng: nanogram; NNRTI: non-nucleoside reverse transcriptase inhibitor; NVP: nevirapine; PI: protease inhibitor.The authors declare that they have no competing interests.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.EP, GP, AC, FDM and PF ideated this case report after observation of the GRT results, and did most of the writing, supported by FS and EM; LC and EP performed RNA sequencing and sequence interpretation; AS and GA contributed the DNA results and critical counselling.


Previous studies have demonstrated a cross-sectional relationship between antiretroviral adherence and HIV virological suppression. We assessed the predictive value of baseline adherence in determining long-term virological failure.We assessed baseline adherence via an adherence questionnaire between administered to all consenting patients attending antiretroviral clinics in Khayelitsha township, South Africa, between May 2002 and March 2004. Virological status was ascertained after five years of follow up and multivariate analysis used to model associations of baseline variables and medication adherence with time to viral suppression or failure.3. We found no statistically significant differences between baseline characteristics and early adherence groups. Multivariate analysis adjusting for baseline CD4 and age found that patients with suboptimal baseline adherence had a hazard ratio of 2.82  for progression to virological failure compared to those whose baseline adherence was considered optimal.Our adherence cohort comprised 207 patients, among whom 72% were female. Median age was 30 years and median CD4 count at initiation was 55 cells/mmOur longitudinal study provides further confirmation of adherence as a primary determinant of subsequent confirmed virological failure, and serves as a reminder of the importance of initial early investments in adherence counseling and support as an effective way to maximize long-term treatment success. The widespread availability of antiretroviral therapy (ART) has changed the course of HIV infection in developed countries, and comparable benefits are observed in resource-limited settings. The provision of effective ART is increasingly understood to be critical for both medical and a public health reasons. Maintaining virological suppression is an important objective for both the individual  and at the population level  and CD4 count (single-platform panleucogating method) were assessed at baseline and every six months according to manufacturer's instructions. Virological failure was defined as two consecutive HIV RNA levels greater than 5000 copies/ml, in accordance with national guidelines. Mortality ascertainment is corrected through linkages with the South African vital registration system 2test and, in the case of small numbers, the Fisher's Exact test. We used Nelson-Aalen cumulative hazards estimates to describe time to confirmed virological failure per adherence group, as this method provides a appropriate summary for failure events 3 or ≥50 cells/mm3), sex , HAART regimen (efavirenz- or nevirapine-based), and age (per 10 years). Multivariate models of associations with virological failure included variables associated with poor adherence in univariate analysis adjusted for potential confounders identified a priori. Hazard proportionality was assessed by analysis of scaled Schoenfeld residuals. All reported p values are exact and 2-tailed, and for each analysis p<0.05 was considered significant. All analyses were performed using STATA version 11.0 .Descriptive analyses were based on percentages and frequencies for categorical variables and medians and interquartile ranges (IQR) for continuous variables. Continuous variables were assessed for skew and as all demonstrated non-normality they were compared using the Wilcoxon rank-sum test. Proportions were compared using the χAll aspects of data collection  were approved by the University of Cape Town Research Ethics Committee. As the data is based out routinely collected data and anonymized, informed consent was not sought.3 (IQR 20–115 cells/mm3) and median HIV-1 RNA levels at initiation was 5.03 log10 copies/mL (IQR 4.3–5.5 log10 copies/mL). Our early adherence assessment found that 181 (87%) patients were considered highly adherent. We found no statistically significant differences between baseline characteristics and early adherence groups  were female. The median age at ART initiation was 30 years (IQR 28–37) years and the majority (80%) received an efavirenz-based regimen. Median CD4 count at initiation was 55 cells/mme groups .In our univariate analysis suboptimal early adherence was the only association with virological failure  . In multOur longitudinal study provides further confirmation of adherence as a primary determinant of subsequent confirmed virological failure, reinforcing the findings of previous studies that associate adherence with viraemia at a single point in time concurrent to or soon after the adherence measures We found that early adherence was a more important predictor of long-term virological suppression than prognostic variables such as CD4 and drug regimens, a phenomenon also observed in better-resourced settings The use of routine viral load monitoring in South Africa enables the exploration of associations with confirmed virological failure. The confirmation of failure, subsequent to a period of adherence optimization, has been shown to identify patients with a high probability of multi-class drug resistance Our study was not able to distinguish whether the association between virological failure and early adherence was due to the early adherence being a marker of long term sup-optimal adherence, or due to ongoing viral replication under selective drug pressure in the early months on ART. Nevertheless, the association we describe validates the structured adherence interventions that are commonplace in the public health approach to ART, including facility-based counseling Several issues need to be considered with respect to the external validity of our findings. First, there is no agreed definition of what constitutes sub-optimal adherence. We applied a conservative cut-off of 95% partly because the drug regimes used did not include boosted protease inhibitors, and partly because of the expectation of poor adherence. Nevertheless, the fact that the majority of our cohort (87%) was considered to be highly adherent is consistent with other findings that display, on average, good adherence within large patient populations As ART programmes mature and lessons emerge over time, concern is growing around the challenges of sustaining long-term adherence