The impact of viral load (VL) decay and cumulative VL on CD4 recovery and AIDS after highly-active antiretroviral therapy (HAART) is unknown.Three virologic kinetic parameters  and cumulative VL during HAART were estimated for 2,278 patients who initiated HAART in the U.S. Military HIV Natural History Study. CD4 and VL trajectories were computed using linear and nonlinear Generalized Estimating Equations models. Multivariate Poisson and linear regression models were used to determine associations of VL parameters with CD4 recovery, adjusted for factors known to correlate with immune recovery. Cumulative VL higher than the sample median was independently associated with an increased risk of AIDS . Among patients with VL suppression, first year VL decay and slope were independent predictors of early CD4 recovery (p = 0.001) and overall gain (p<0.05). Despite VL suppression, those with slow decay during the first year of HAART as well as during the entire therapy period , in general, gained less CD4 cells compared to the other subjects  even after adjusting for potential confounders.In a cohort with free access to healthcare, independent of established predictors of AIDS and CD4 recovery during HAART, cumulative VL and virologic decay patterns were associated with AIDS and distinct aspects of CD4 reconstitution. The initial goal of highly-active antiretroviral therapy (HAART) was to improve AIDS-free survival and attempt to mitigate the harmful effects of treatment. Immune reconstitution via CD4 recovery served as an intermediate marker for response to HAART because of its predictive capacity for AIDS events and death.Even among patients reaching these virologic targets, there are significant inter-individual differences in the recovery of CD4+ T cells and risk of clinical events, suggesting that other factors may relate to these outcomes.The U.S. Military HIV Natural History Study (NHS) is a prospective multicenter observational study of HIV-infected active duty military personnel and other beneficiaries  from the Army, Navy/Marines and Air Force. Seroconverters (SC) were defined as patients having a documented HIV seronegative date prior to the first positive HIV date see . The estParticipants who provided written informed consent and initiated HAART through July 1, 2008 regardless of regimen continuation were included in the present study. The NHS and this substudy have been approved by each center's Institutional Review Board and the Uniformed Services University of the Health Sciences Institutional Review Board.A primary aim of this study was to capture and summarize the overall and early VL dynamics in such a manner as to permit their eventual use in clinical practice. In that regard, we made the following assumptions: i) by the time HAART is typically initiated for an individual in the NHS a natural steady state VL exists; ii) once potent HAART is initiated there is a rapid decline in the VL followed by a slower decline; and iii) such a typical pattern of VL can be explained on the basis of an exponential decay in the circulating VL. The definitions of the parameters used in this study are shown in We computed four VL parameters at the level of each individual: (i–ii) exponential decay constant of VL change during entire duration of HAART  and during the first year of HAART, respectively; (iii) VL slope during the first year of HAART obtained using linear Generalized Estimating Equations (GEE) models; and (iv) cumulative VL . The VL + T cell count and VL data for all subjects to generate time-trend lines or curves using linear and non-linear GEE models, assuming an equal correlation structure. The time-trend curves derived by non-linear GEE modeling were refined further using spline smoothed curves with knots at the end of each year since HAART initiation. The resulting curves describe an overall or composite VL pattern for the cohort.The cohort-level analyses made use of all available CD4We estimated the parameters detailed in Characteristics of the 2278 participants who initiated HAART are in The cohort-level trajectories in CD4 counts during HAART revealed two phases of CD4 count changes In phase I, for all subjects initiating HAART there was a rapid increase in CD4 counts during the first two years, followed in phase II by a slower, sustained gain in CD4 cells . We straThe association of the three VL kinetic parameters and cumulative VL with risk of developing AIDS during HAART was evaluated in separate multivariate models adjusted for length of follow up. For these and the other analyses described later, we dichotomized subjects based on the VL parameters using the median value of the parameter as the cut-off. We included into each multivariate model additional covariates that have been shown to be predictive of immunologic recovery during HAART, including time to VL suppression .[26], [3The slope and exponential decay constant for VL during the first year of HAART were not predictive of AIDS, whereas a slower overall VL decay showed a statistical trend towards predicting AIDS during HAART, independent of the other covariates . A higher than average cumulative VL during HAART  was associated with the greatest risk of developing AIDS. These results were similar when the VL parameters were estimated excluding the VL measurements recorded after the AIDS event occurred  or when In separate analyses, where attainment of VL suppression at any point during HAART was replaced with VL suppression by 6 or 12 months, overall VL decay constant was a significant independent predictor of AIDS in patients who attained VL suppression at 6  and 12  months, whereas in these models, the VL slope or exponential VL decay during the first year were not predictive of AIDS. The cumulative VL remained highly predictive of AIDS risk in those who attained VL suppression during 6  and 12  months of HAART. Collectively, these data indicated that a slow overall VL exponential decay and a high cumulative VL during HAART increased AIDS risk after initiation of HAART.We next determined whether the VL kinetic and other parameters that were included in the models to assess AIDS risk during HAART also associated with the rate of CD4 gain . We founThe aforementioned data suggested that a slower VL decay during the first year of HAART is associated with both a reduced rate of CD4 gain in the first two years of HAART and overall gain in CD4 cells . By contNotably, VL suppressers categorized to the slow/slow decay group had a significantly muted CD4 recovery during HAART compared with all other subjects . ConcordNot all patients on HAART display robust CD4 cell gains, despite VL suppression.The pre-HAART VL predicted the subsequent rate of decay during the first year of HAART. Since most patients were able to achieve suppression by 6–12 months, it is not surprising that the rate of decay would be greater for patients with higher initial VLs. This may also suggest that patients with higher initial VLs have a larger proportion of actively replicating, productively-infected cells that are more susceptible to HAART. This is consistent with previous studies that examined decay for patients receiving HAART.Although the importance of early virologic suppression and virologic failure on CD4 recovery has been well-described,Even among subjects who attained VL suppression, and after adjustment for time to VL suppression, a slow overall VL decay was predictive of late/long-term CD4 changes , but not early CD4 changes (rate of CD4 gain during the first two years of HAART). In contrast, a slower VL decay within the first year of HAART associated with early but not later/long-term CD4 changes during HAART. These results suggest that, although among VL suppressers the pace and extent of CD4 gain during the early phases of HAART may be highly correlated with both the early and overall VL decay patterns, durable gains in CD4 cells after two years of HAART may be highly dependent on the overall VL decay pattern. These findings demonstrated that VL suppressors could be stratified into two categories such that those with both a slow early and overall VL decay  will achieve CD4 recovery, but the gain in CD4 cells would be significantly muted relative to all other subjects . BecauseThe association of the extent of CD4 recovery was strongest with the overall VL decay and not the first year VL decay or the cumulative VL, suggests that these VL parameters may be capturing different aspects of VL changes during HAART (early trajectory and maintenance of suppression). The overall decay provides information throughout the duration of treatment and is not limited to one year of information. Hence, it is probable that the decay pattern occurring after virologic suppression (third phase of VL decay)In contrast to the overall decay pattern, the cumulative VL is a coarse measure of overall VL burden  during HAART and does not account for VL decay patterns. For example, a patient who suppresses early but has late rebound might have a comparable cumulative VL to that of a patient with predominantly late virologic suppression. This may partly explain why this parameter as computed may not associate strongly with CD4 recovery. However, another explanation hinges on the use of detectable VLs to compute this parameter. Certainly, patients with complete or repetitive virologic rebounds may experience a loss of CD4 recovery; however, the vast majority of patients in this cohort achieved suppression within the first year and the rate of rebound was low.We investigated a large number of prospectively evaluated subjects who have equal access to healthcare and high rates of adherence to HAART.In summary, our findings underscore that the early and overall patterns of VL decay among VL suppressed patients is an independent determinant of CD4 recovery. In addition, the cumulative VL is a determinant of AIDS risk during HAART. Thus, inter-individual differences in VL decay patterns may partly explain the wide variability in CD4 recovery even among those individuals achieving VL suppression within the recommended timeframe. These results also suggest that regimens that produce the most rapid virologic decay and durable suppression could lead to better clinical/immunologic responses. These parameters could be further developed to enhance clinical trial assessment of ARV regimens and assist clinicians with identifying patients at risk for adverse events beyond standard indicators.Table S1Definitions for various parameters used in this study.(DOCX)Click here for additional data file.Table S2Modeling of VL kinetics based on tertiles of pre-HAART VL.(DOCX)Click here for additional data file.Table S3Association of VL parameters with risk of AIDS development after initiation of HAART among seroconverters.(DOCX)Click here for additional data file.Note S1Statistical concepts in VL parameter estimation.(DOCX)Click here for additional data file.


Etravirine (ETR) was approved for patients with virological failure and antiretroviral resistance mutations. It has also shown antiviral efficacy in antiretroviral-naïve patients. However, data on the switching from protease inhibitors (PI) to ETR are lacking.HIV-1-infected patients with suppressed viral load (VL) during a PI-containing regimen (>12 months) and no previous virological failure were randomized to switch from the PI to ETR   or to continue with the same regimen . Percentage of patients with VL≤50 copies/mL were assessed at week 48, as well as changes in CD4 T-cell counts and metabolic profile.We included 43 patients . Two patients receiving ETR (grade-1 diarrhea and voluntary discontinuation) and another in the control group (simplification) discontinued therapy early. No patients presented virological failure (two consecutive VL>50 copies/mL); treatment was successful in 95.2% of the control group and 90.9% of the ETR group  (p = 0.58). CD4+ T-cell counts did not significantly vary [+49 cells/µL in the ETR group (p = 0.25) and −4 cells/µL in the control group (p = 0.71)]. The ETR group showed significant reductions in cholesterol (p<0.001), triglycerides (p = <0.001), and glycemia (p = 0.03) and higher satisfaction  (p = 0.04). Trough plasma concentrations of ETR were similar to observed in studies using ETR twice daily.Switch from a PI-based regimen to a once-daily combination based on ETR maintained undetectable VL during 48 weeks in virologically suppressed HIV-infected patients while lipid profile and patient satisfaction improved significantly.NCT01034917ClinicalTrials.gov  Etravirine is a second-generation non-nucleoside analog reverse transcriptase inhibitor (NNRTI). It was approved by the U.S. Food and Drug Administration and the European Medicines Agency in 2008 for clinical use in adults with incomplete virologic suppression and resistance to multiple antiretroviral agents, including previous NNRTI, in combination with a ritonavir-boosted protease inhihitor (PI) The clinical recommendation for market authorization of etravirine was mainly based on the results of 2 pivotal phase 3 studies, DUET-1 and DUET-2 Since pharmacokinetic studies support the use of etravirine once daily We designed a pilot study to test the efficacy and safety of switching from a PI to etravirine as an antiretroviral switching strategy in patients with a suppressed viral load. Our approach was based on the high antiviral potency and high genetic barrier to resistance of etravirine, as well as the favorable safety profile and patient-friendly dosing (once daily dose and dissolved in water).The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Written informed consent was obtained from all participants.We performed a 48-week, prospective, randomized, pilot study in HIV-1-infected outpatients. The study candidates were all those patients receiving standard triple-drug highly active antiretroviral therapy (HAART) including a PI for more than 12 months, with an undetectable viral load (VL <50 copies/mL) for more than 6 months and no documented resistance to NNRTIs or NRTIs or virological failure with previous regimens. For therapy to be switched to etravirine, patients had to fulfill at least 1 of the following criteria: dyslipidemia , antiretroviral-related gastrointestinal disturbances, or a repeatedly expressed dissatisfaction with the current antiretroviral regimen.Participants were randomly assigned in a ratio of 1∶1 to switch from the PI to etravirine  or to continue with the same PI-based regimen (control group). The treatment allocation list was generated by blocks using numbers drawn from the uniform distribution.Patients were assessed at week 0 (baseline) and weeks 4, 12, 24, 36 and 48. The laboratory data recorded at these time points included plasma HIV-1 RNA, CD4 and CD8 T-cell counts, biochemistry (fasting conditions) including a complete lipid profile .Virological failure was defined as the viral rebound . HIV-RNA was determined using the AMPLICOR HIV-1 MONITOR Test, v 1.5 .HIV-related data  were recorded from the patient’s records.Adverse events and reasons for discontinuation were also recorded at the same time points. Adverse events were classified according to the definitions of the World Health Organization. Reasons for discontinuation were classified as follows: virological failure, adverse events (grade 1–2 or 3–4), death, or any other cause .Patient satisfaction with therapy was assessed using two 0–10 Likert scales (satisfaction with treatment and preference for treatment) at baseline and weeks 24 and 48.Etravirine trough concentrations in plasma were also determined at week 12 in all patients who were receiving the drug.The principal efficacy analyses (proportion of patients who maintained HIV-1 RNA ≤50 copies/ml at week 48) were performed on-treatment and intention-to-treat . Additionally, variations in CD4 and CD8 T-cell count at each time point from baseline were also compared between groups, as well as changes in metabolic parameters (lipid metabolism and glucose) and liver enzimes. Changes in lipid parameters after switching to etravirine were also evaluated according to the PI used at baseline. Safety was assessed by comparing the percentage of patients who discontinued the study during the 48 weeks of follow-up and the percentage of patients with serious adverse events (grade 3–4).Patient satisfaction with treatment at weeks 24 and 48 was compared between treatment arms and also by stratifying participants according to the reason for switching at baseline.Etravirine trough concentrations in plasma were described and compared with historical data from studies including subjects taking etravirine not dissolved in water.The analysis of the study included comparisons between baseline and weeks 4, 12, 36 and 48 in each group and comparisons between groups (control versus ETR group) at each visit point.t test; non-normally distributed variables were compared using the Mann-Whitney test. The dependent t test for paired samples or the Wilcoxon signed rank test was performed to assess the significance of changes observed over time. The chi-square test or Fisher exact test was used as appropriate to compare discrete variables.Quantitative variables were expressed as the mean and standard deviation (SD) or as the median and interquartile range (IQR); qualitative variables were expressed as frequencies and percentages. Normally distributed continuous variables were compared using the Statistical analysis was performed with the SPSS 15.0 program .The study sample comprised 43 patients: 22 in the ETR group and 21 in the control group.Epidemiological, clinical, and HIV-related characteristics were summarized in The main reasons for participating in the study were dyslipidemia (48.8%), followed by low satisfaction with the previous regimen (twice-daily dosing and need to store ritonavir in a refrigerator) (39.5%) and gastrointestinal disorders (11.6%) . At baseThe percentage of patients who maintained HIV-1 RNA ≤50 copies/ml at week 48 was similar between the groups, with no significant differences; 100% of patients who completed the study maintained HIV-RNA ≤50 copies/mL at week 48 in both groups, respectively (p = 0.84) . The proportion in the intention-to-treat analysis (missing = failure) was 95.2% in the control group and 90.9% in the ETR group (p = 0.96). Difference of proportions between groups with 95% CI was 4.33.Mean (SD) CD4 T-cell counts in the ETR group increased from 702 (333) to 749 (345) cells/µL, although the difference did not reach statistical significance (p = 0.25), and did not vary in the control group . No statistically significant differences were recorded between groups at any time point (p = 0.71 at week 48).Patients from the ETR group showed significant reductions in cholesterol , triglycerides , and glycemia  . DiffereWhen patients were stratified according to the PI used at baseline, a significant improvement was observed at week 48 in total cholesterol, triglycerides, and glycemia in patients who switched from lopinavir/ritonavir to etravirine . A significant difference was also observed in triglycerides in patients who switched from atazanavir (p = 0.04) and in glycemia in those who switched from fosamprenavir (p = 0.04).When patients were stratified according to the presence of dyslipidemia or not at baseline, no difference were seen in lipid parameters .Therapy was discontinued early by 2 patients receiving etravirine (1 case of diarrhea (grade 1) and 1 voluntary discontinuation) and in 1 patient in the control group (change of regimen to simplify). No serious clinical adverse events (grade 3–4) were reported during the study.No significant changes in liver enzymes were observed in either group, and no grade 3–4 elevations were recorded. No differences were seen between the groups at week 48 .Mean (SD) patient satisfaction rose from 7.7 (1.4) at baseline to 8.9 (1.3) at week 24 and 9.2 (1.4) at week 48 in the ETR group; these values decreased slightly in control patients from 6.0 (2.3) to 5.6 (2.4) and 5.3 (2.1), respectively . DiffereThe mean (range) etravirine trough concentrations in plasma was 569.3 (202–1141) ng/mL. Interpatient variability (% coefficient of variation) in etravirine concentrations was 50.5%.Etravirine-based regimens could prove to be an excellent switching strategy in virologically suppressed HIV-infected patients thanks to their safety profile and patient-friendly dosing. Nonetheless, data on etravirine in this scenario are scarce.At the end of the 1990s, many studies compared the antiviral outcome of an NNRTI (nevirapine or efavirenz) with the PIs used at the time Nonetheless, despite its good safety profile, no experience has been reported with etravirine as an alternative therapy for simplification in virologically suppressed HIV-infected patients taking a ritonavir-boosted PI. The main reasons for switching from PIs in the clinical practice include PI-related laboratory toxicity , clinical disorders , and dosing-related conditions. In our study, the main reasons for switching were dyslipemia  and low satisfaction with the previous regimen (twice-daily dosing and the need to store ritonavir in a refrigerator) (around 40%). The low rate of patients who switched because of gastrointestinal disorders (11.6%) indicates that current regimens are generally well tolerated. The most frequently switched PI was atazanavir/ritonavir (56%), since, at the initiation of the study, ritonavir had to be kept in a refrigerator (a complaint from many patients).Although this is a pilot study, our results revel that the switch from a PI to etravirine maintains virological suppression after 48 weeks of follow-up. No patients experienced viral rebound in either treatment arm. Moreover, CD4 T-cell counts increased slightly in patients who switched to etravirine. Although this increase was not statistically significant, it could be clinically relevant in some patients, especially in those with low CD4 T-cell counts.As expected, and consistent with previous data for the effect of etravirine on lipid profile As for safety, the low rates of early withdrawal in the ETR arm that were similar to those in the control group support previous data on the good tolerability and low toxicity of etravirine As patient satisfaction is generally high with current antiretroviral combinations, it is usually difficult to demonstrate differences after a switch. Among our patients, however, satisfaction improved significantly after switching to etravirine , specifically in those with gastrointestinal disturbances at baseline. Nonetheless, some patients did not consider 4 tablets of etravirina (used in the study) plus the rest of the nucleoside backbone a simplified regimen. Marketing of 200-mg etravirine tablets has recently been approved in North America and in Europe. This new formulation will facilitate dosing and, consequently, patient acceptance and satisfaction. In addition, plasma concentrations of etravirine, administered once daily dissolved in water, were in the same range to those observed in subjects receiving undispersed etravirine tablets The limited sample size of the study does not permit to strongly state our conclusions but this pilot study provides initial data about the use of an etravirine-based regimen as a possible strategy in subjects with PI-associated toxicities or dissatisfied with their regimens. Additionally, this exploratory study allows us to establish guidelines for future studies with more patients. The randomized and controlled study designs, however, are both strengths of the study that becomes our results in useful information.In conclusion, this randomized trial seems to demonstrate the maintenance of antiviral efficacy 48 weeks after switching from a PI to etravirine. Our results also confirm the favorable safety profile of etravirine, which has a lipid-friendly profile that is similar to that of the other commercialized NNRTIs and better than that of PI-containing regimens. Consequently, etravirine could be considered as an alternative in virologically suppressed HIV-infected patients receiving a PI-based antiretroviral combination and who have not experienced failure with other NNRTI-based regimens, mainly in those with metabolic disturbances.Protocol S1(DOC)Click here for additional data file.Checklist S1(DOC)Click here for additional data file.


In resource-limited settings where viral load (VL) monitoring is scarce or unavailable, clinicians must use immunological and clinical criteria to define HIV virological treatment failure. This study examined the performance of World Health Organization (WHO) clinical and immunological failure criteria in predicting virological failure in HIV patients receiving antiretroviral therapy (ART).In a HIV/AIDS program in Busia District Hospital, Kenya, a retrospective, cross-sectional cohort analysis was performed in April 2008 for all adult patients (>18 years old) on ART for ≥12 months, treatment-naive at ART start, attending the clinic at least once in last 6 months, and who had given informed consent. Treatment failure was assessed per WHO clinical (disease stage 3 or 4) and immunological (CD4 cell count) criteria, and compared with virological failure .Of 926 patients, 123 (13.3%) had clinically defined treatment failure, 53 (5.7%) immunologically defined failure, and 55 (6.0%) virological failure. Sensitivity, specificity, positive predictive value, and negative predictive value of both clinical and immunological criteria (combined) in predicting virological failure were 36.4%, 83.5%, 12.3%, and 95.4%, respectively.In this analysis, clinical and immunological criteria were found to perform relatively poorly in predicting virological failure of ART. VL monitoring and new algorithms for assessing clinical or immunological treatment failure, as well as improved adherence strategies, are required in ART programs in resource-limited settings. Substantial progress has been made over the last several years in the number of people receiving antiretroviral therapy (ART) for HIV/AIDS treatment. From a baseline of approximately 400,000 people receiving ART in low- and middle-income countries (LMICs) in December 2003, more than 5 million people were receiving treatment by the end of 2009 High mortality in the early months of treatment In LMICs where routine viral monitoring is limited, clinicians follow WHO recommendations to define treatment failure In this study we analyzed the performance of WHO criteria for clinical and immunological failure as surrogate measures for virological treatment failure in a context where VL testing is not widely available.In 2003, Médecins Sans Frontières (MSF) began an ART program in Busia District Hospital, Kenya. Protocols for HIV testing and treatment followed 2006 WHO and Ministry of Health (MOH) guidelines. By December 2008, around 2,000 patients were started on treatment at the district level and 1,500 at the rural level in primary health clinics.st line therapy  for ≥12 months; ARV-naïve at treatment start; who attended the clinic at least once within the previous 6 months; and given informed consent to participate in the study, were considered eligible for the study.From April to September 2008 a cross-sectional survey was conducted. Adults (>18 years old) currently receiving a triple antiretroviral (ARV) drug regimen classified as standard 1All patients meeting the inclusion criteria were placed on a list that was distributed to the clinicians. In addition, a note was added to the front of the medical file for each included patients. If an included patient was attending for a routine visit, the risks and benefits of the study were explained to the patient.Clinical outcomes were determined based on data routinely recorded in the patients files using data collection software called FUCHIA . The data included hospitalization during ART and the occurrence or recurrence of selected WHO stage 3 or 4 conditions during ARV therapy diagnosed by clinical officers trained in HIV care including: weight loss of >10%, pulmonary or extra pulmonary tuberculosis, cryptococcal meningitis, toxoplasmosis, chronic herpes simplex infection, Kaposi’s sarcoma (KS), pneumocystic pneumonia (PCP), HIV wasting syndrome, severe bacterial infections, recurrent severe bacterial pneumonia, lymphoma, persistent oral candidiasis, sepsis/septicaemia, or HIV encephalopathy.Diagnostic capacities were limited at Busia Hospital, X-ray and acid-fast bacilli in sputum smear were available for TB diagnosis; but specimen culture was unavailable. Lumbar puncture and cerebrospinal fluid latex test  was used for the diagnosis of cryptococcal meningitis. All other opportunistic infections were diagnosed based on clinical findings.On the day of enrollment, a venous blood sample of 10 mL was taken from each patient and divided into two parts: one tested for CD4 cell count at the Busia laboratory using FACSCount flow cytometry , and the other sent to Kenya Medical Research Institute (KEMRI) in Nairobi, Kenya, where VL testing was performed using NucliSENS EasyQ HIV version 1.2 , with limit of detection of 50 copies/mL.The treatment protocol of the Busia program recommended measuring CD4 cell count every 6 months and VL in patients with either clinical or immunological failure any time after 12 months on ART. Definitions for treatment failure followed 2006 WHO guidelines. Immunological failure was confirmed with a second CD4 measurement.For the study, treatment failure based on CD4  criteria was defined as either CD4 count below the patient’s baseline measurement at 6 months of therapy, CD4 count less than 50% of peak measurement at any time after 6 months of therapy, or CD4<100 cells/µL after 12 months of therapy st line treatment initiation Treatment failure based on clinical criteria was defined as the occurrence of either new or recurrent disease of WHO clinical stage 3 or 4 at least 6 months after 1Virological failure was assessed by measuring viral load (VL). WHO defines virological failure as plasma HIV-1 RNA level >5,000 copies/mL after 6 months of treatment, if adherence is considered adequate P values of <0.05 were considered statistically significant.Data were entered in FUCHIA software  and exported to and analyzed with SPSS version 18 . Data variables were tabulated and analyzed using chi-square and Fisher’s exact tests. This study was approved by the Ethics Review Boards of MSF and KEMRI. Only patients who gave informed consent to participate in the study were included in this analysis.As of the middle of April 2008, 1,037 out of the 3,471 patients on ART in the MSF Busia HIV/AIDS treatment program were deemed eligible for the study. Those excluded were 1,115 patients on ART <12 months, 344 non-naïve for ART or started on ART other than first line, 305 who died, 358 lost to follow up and 312 who were <18 years old.After a second analysis of the eligible group, 111 patients were excluded; 13 patients were non-naïve or started on ART other than first line, 71 were lost to follow-up, 14 transferred out during the study, 4 died, 8 declined to participate, and one was on ART <12 months, resulting in 926 patients for the analysis. .2  were female. At the start of ART, median age was 38.3 years (interquartile range [IQR] 32.1–44.6); 724 (76.3%) patients were WHO clinical disease stage 3 or 4; the median CD4 cell count was 133 cell/µL [IQR 68–193]; and 255 (27.5%) patients had a body mass index (BMI) <18.5 kg/m2 .At the time of study, median CD4 count was 489.4 cells/µL, the median CD4 gain from baseline was 346.4 cells/µL, and median time on ART was 38 months [IQR 33.8–45.0].ART regimens administered at time of inclusion were d4T/3TC/NVP in 892 (96.3%) patients, d4T/3TC/EFV in 32 (3.5%), and AZT/3TC/NVP in 2 (0.2%), all in standard dosage and qualified fixed-dose combination as per WHO recommendations.At the time of the study, 123 (13.3%) of 926 patients had clinically defined treatment failure, 53 (5.7%) experienced treatment failure based on CD4 cell count criteria, and 55 (6.0%) had virological failure  per 2010 WHO definition .Of the patients with clinical failure, 49 (39.8%) had weight loss of >10%, and 73 (59%) had tuberculosis. Opportunistic infections were common; bacterial pneumonia, was reported in 16 (13%) patients, while cryptococcal meningitis and brain toxoplasmosis in 1.6% of the patients.At time of study, 274/924 (29.7%) of the cohort had detectable VL ; 650 (70.3%) had <50 copies/ml and 776 (83.9%) did have <400 copies/ml. Of the patients with detectable VL, 46% (126/274) had between 50–399 copies/mL . Of the Comparison of means and proportions were carried out using Mann-Whitney U test and chi square test respectively. The patients who developed a virological failure were statistically younger than the ones who did not develop it (p<0.01). Year of ART initiation was significantly associated with a reduced risk of developing a clinical failure in univariate analysis and it is remained significant also after adjustment for possible confounders in multivariate analysis (p<0.01).For 773 and 873 patients has been possible to draw a Kaplan Meier analysis respectively from six months of therapy to clinical and immunological failure. The mean time before developing clinical failure is 54.5 months  and for immunological failure is 58.6 months . , 3.Sensitivity of immunological and clinical WHO criteria to define treatment failure was 23.6% and 18.2%, respectively, compared with virological failure . When coSpecificities for immunological, clinical, and both together for predicting virological failure were 95.4%, 87.0%, and 83.5%, respectively.Positive predictive values (PPV) for immunological and clinical criteria to define virological failure were 24.5% and 8.1%, respectively. When both criteria were analyzed together, PPV was 12.3%. Negative predictive values (NPV) were 95.2%, 94.4%, and 95.4%, respectively, for immunological, clinical, and both criteria.In our study we found a relatively low proportion of virological failure (6.0%) following 2010 WHO definition (VL >5000 copies/ml) in patients on ART for more than 12 months as reported in other LMICs, supporting the fact that ART can be provided in resource-poor settings with favorable outcomes In this study, the PPV of clinical or immunological monitoring for detecting virological treatment failure was relatively low. Mee et al reported a PPV of CD4 count of 36.8% while Kaiser et al recorded PPV ranging from 9.5%–28.7%. Low sensitivity of clinical and immunological criteria to define treatment failure highlights the need for improved methods to detect treatment failure in the absence of VL testing. In our study, only 8.1% of patients with clinical failure and 24.5% of those with immunological failure were found to have virological failure.Only 3/55 (5.45%) of patients with confirmed virological failure met both clinical and immunological criteria for treatment failure, and 35/55 (63%) of the patients with virological failure did not meet both clinical and immunological definitions of failure, showing that patients with VL >5,000 copies/mL might not meet any of the currently used criteria to detect treatment failure. Many treatment failures may therefore be missed using only clinical and immunological criteria, which could lead to accumulated resistance in patients who continue on failing regimens.An evaluation from resources limited countries found no evidence of improved mortality in programs with viral load test, though follow-up was short. These results from a Kenyan ART program also illustrate the difficulties faced by other African countries in implementing the new WHO recommendations for ART initiation Follow-up of patients with VL measurements seems to be the only way to adequately monitor the patients, and VL appears to be the most reliable tool for deciding when to switch failing regimens for patients A strength of our study was in the assessment of clinical outcomes since they were systematically collected in patient’s files, allowing us to examine the correlation between clinical and immunological criteria together with viral load measurement. Another strength of the study was that it was done in a routine ART program in a resource-limited setting including decentralized rural clinics, which reflects the reality of other sub-Saharan African countries.A limitation of the study lay in not being able to analyze adherence despite the data obtained through questionnaires since it was impossible to find standard definitions using the current self-reported and visual-analogue scale. Another study weakness was the limited diagnostic capacities for the main opportunistic infections seen in our program, which could bias some of the clinical events registered.This study builds on existing literature and builds the case that clinical and immunologic criteria, given low sensitivity, allow for individuals to switch to expensive second-line who may not have true virological failure.In conclusion, these data illustrate the urgent needs for new or improved algorithms for measuring clinical or immunological treatment failure and wider access to VL monitoring in low-resource settings. Using current WHO immunological and clinical criteria to determine virological treatment failure is inadequate in a setting were VL is not widely available and second-line ART options are limited.


The availability of raltegravir plus atazanavir provides an alternative antiretroviral strategy that may be equally efficacious and less toxic than those currently recommended in HIV treatment guidelines. In fact, this new combination antiretroviral therapy attracts the attention of the scientific community because both drugs have a good safety profile coupled with potent antiviral activity, and their combined use would avert nucleoside- and ritonavir-related toxicities.We describe the case of a 47-year-old, Caucasian woman treated for HIV-1 infection who developed Buffalo Hump during antiretroviral therapy, including raltegravir and unboosted atazanavir. Clinical evaluation and an ultrasonography scan of the cervical region showed a new progressive increase of lipohypertrophy and the results of DEXA confirmed these data. In our patient the worsening of the Buffalo Hump cannot be attributed to hypercortisolism; insulin-resistance, diabetes, dyslipidemia, hyperlactatemia and metabolic syndrome were not present. Moreover, she was not in therapy with antiretroviral drugs that are described as the cause of Buffalo Hump; on the other hand she developed this side effect three months after the switch of the antiretroviral therapy to raltegravir plus unboosted atazanavir.Current data indicate that the etiology of HIV-associated Buffalo Hump remains elusive but is likely multifactorial; a possible contributing cause, but not the main cause, could be exposure to antiretroviral drugs. To the best of our knowledge, this is the first report on development of Buffalo Hump in the course of antiretroviral therapy, including the use of these drugs. On the basis of our data we can formulate the hypothesis of a pharmacological pathogenesis that underlies the development of this case of Buffalo Hump in the absence of other risk factors. Furthermore, the combination is well tolerated and has a low incidence of adverse effects [et al. during a study in healthy subjects were generally "mild-to moderate" in intensity. Common side effects seen when both drugs were taken were jaundice and headache [et al. evidenced that after five to seven months of therapy based on RAL plus ATV no patients discontinued treatment due to drugs used in therapy, adverse events, and no one had a grade 3 or 4 lab toxicity [Antiretroviral (ARV) treatment guidelines currently recommend ARV regimens containing a Nucleos(t)ide Reverse Transcriptase Inhibitors (N(t)RTIs) based backbone with a Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI) or ritonavir boosted Protease Inhibitor (PI/r). However, significant toxicity has been associated with N(t)RTI(s) and PI/r containing regimens. Recent data presented by Gupta  effects . Moreoveheadache . RipamonWe describe the case of a 47-year-old, Caucasian woman treated for HIV-1 infection, who developed buffalo hump during antiretroviral therapy consisting of RAL and unboosted ATV. She was diagnosed with HIV disease in February 1999: the CD4+ cell count was 214/mm3 (11%) and the HIV viral load was 253,200 copies/ml at that stage. An initial highly active antiretroviral therapy (HAART) regimen consisted of zidovudine, lamivudine and indinavir. After 18 months, the therapy was changed to stavudine, lamivudine and nevirapine because of an episode of acute renal colic. Our patient attended outpatient clinics on a regular basis, and was found to have a good immunological and virological response to HAART. By July 2004, she presented with a progressive peripheral fat loss; facial lipoatrophy was apparent but not severe. For these reasons the HAART combination was changed (November 2004), and stavudine was replaced by a nucleotide analogue tenofovir. The CD4+ count was 599/mm3 (16%) and the HIV viral load was < 50 copies/ml at the change of the antiretroviral medications. She was on nevirapine and lamivudine plus tenofovir for five years with a good immune-virological response. We observed neither other fat accumulation nor fat loss and no significant metabolic disorders after the switch. Body Mass Index (BMI), glucose, cholesterol, triglyceride, plasma cortisol and insulin concentrations were normal.In November 2009 the patient presented with a HIV viral load of 1551 copies/ml; a subsequent test of resistance showed the presence of K65R, K103S, M184V, and G190A. Because she refused therapies with an increased risk of metabolic alterations, the antiviral treatment was changed to RAL 400 mg with unboosted ATV 200 mg twice daily.Three months later, it was noted that she developed a new progressive increase of lipohypertrophy of the dorso-cervical region of the neck. There was no localized accumulation of fat in her abdomen and in the submental region of her neck. The hump in the back of her neck was causing neck pain, headaches off and on and sleep apnea. It was causing her discomfort and affecting the motion of her neck. An ultrasonography scan of the cervical region reported a large amount of subcutaneous fat around the posterior aspect of the neck Figure . The resIn the next three months she developed a massive lipohypertrophy of the dorso-cervical region of her neck. For this reason the plastic surgery staff proposed surgical removal of the BH due to discomfort, localized pain and the progressive increase of lipohypertrophy of the dorso-cervical region of the neck. The patient refused this option and six months later we observed a stabilization of the subcutaneous fat of the cervical region.et al. reported that Buffalo Hump adipose tissue shows specific disturbances in gene expression with respect to subcutaneous fat from HIV-1-infected/HAART-treated patients [et al. reported that patients with Buffalo Hump had higher BMI and more total limb and abdominal fat than patients without Buffalo Hump. Current data indicate that a possible contributing cause, but not the main one, could be exposure to antiretroviral drugs: risk factors for Buffalo Hump are longer duration of use of protease inhibitors and longer duration of use of zidovudine [et al. showed that Buffalo Hump was associated with treatment with saquinavir, indinavir, efavirenz, tenofovir and stavudine. Moreover, time of exposure to stavudine and fat loss, one of stavudine's major side-effects, were associated with Buffalo Hump [Buffalo Hump is commonly reported in adults with HIV-associated lipodystrophy. Accumulation of fat over the dorso-cervical spine is reported in 2% to 13% of HIV infected patients with a higher prevalence 6 to 13%) in those showing any other feature of the lipodystrophy syndrome . The patpatients . Some re to 13% ipatients . The clodovudine . Palacioalo Hump . Previoualo Hump ,5.We report the development of the Buffalo Hump cannot be attributed to hypercortisolism; insulin resistance, diabetes, dyslipidemia, hyperlactatemia and metabolic syndrome were not present. Moreover, there were no significant changes noted in our patient's diet, body weight and BMI. Her lifestyle was normal and she followed a regular exercise program.At the moment she is not in therapy with antiretroviral drugs that are described as the cause of Buffalo Hump; on the other hand she developed this side effect three months after the switch of the antiretroviral therapy to RAL plus unboosted ATV. A caveat of this report is that she had a history of exposure to antiretroviral drugs  associated with the development of Buffalo Hump. This condition may have predisposed the patient to develop the disorder and could constitute a background that contributes to the final appearance of buffalo hump after raltegravir plus atazanavir treatment. Current data indicate that the etiology of HIV-associated Buffalo Hump remains elusive but is likely multifactorial and includes, metabolic disorders, genetic factors, receipt of ART and HIV infection itself .The availability of RAL and ATV provides an alternative ARV strategy that may be equally efficacious and less toxic than those currently recommended in HIV treatment guidelines. However, there are few data in the literature available to date regarding such a combination. There are no publications today that describe a relationship between RAL and unboosted ATV therapy and the occurrence of Buffalo Hump. This is the first report on the development of Buffalo Hump in the course of antiretroviral therapy including these drugs: on the basis of our data we can formulate the hypothesis of a pharmacological pathogenesis that underlies the development of this case of Buffalo Hump in absence of other risk factors. More investigation is required to determine if RAL plus unboosted ATV is a safe alternative to RTV boosted PI based ARV strategies and if there are significant side effects related to this ARV treatment.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.GC has made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data. GD was involved in drafting the manuscript or revising it critically for important intellectual content. FM and CR made substantial contributions to the acquisition of data. CMM, BC and VV gave final approval of the version to be published. All authors have read and approved the final manuscript.


Adherence to treatment instructions with antiretroviral therapy (ART) is very crucial for successful treatment outcome. However, sticking to treatment instructions pose-great challenges to HIV/AIDS patients. This cross-sectional study was on HIV infected adults attending ART clinic in Nigeria to explore nonadherence factors in relation to their socioeconomic characteristics. Validated structured questionnaire was administered to 221 participants. Results showed a high nonadherence rate of 85.1%. The commonest occurring factors of non-adherence were forgetfulness (53.8%), busy schedule (38.8%), side effects of drugs (31.9%), and stigma (31.9%). Males were more likely to complain from busy schedule, feeling healthy, fear of partner disclosure, long waiting period, and long term regimen. Patients with no formal education were more likely to attribute non-adherence to poor communication, side effects of drugs, and stigma. Employed patients seemed to miss their drugs more than the unemployed and artisans. The high non-adherence rate has serious implications for the control of HIV in infected individuals and management of HIV in general. Nurses should intensify efforts on patient education and counseling. HIV/AIDS is one of the major public-health problems worldwide, affecting mostly people who are at the most productive stage of life. Out of the estimated 34 million people living with HIV/AIDS globally as at the end of 2010, 68% reside in Sub-Saharan Africa [The development and availability of antiretroviral therapy (ART) became a turning point in the control and prevention of the epidemic. With the success of ART in improving the quality of life of PLWH and reducing morbidity and mortality, HIV has become a chronic manageable disease . StudiesIn Nigeria ART was commenced  in 2002 and coverage stood at 359,181 in 2010  refers tμL, regardless of symptom. On each appointment, CD4 + T cell count is repeated and adherence to drug is ascertained by pill count of the previous supply. Effort is made through counseling to retain each client on the first line drugs due to their benefits because the second line drugs have more side effects. Various health care providers—including clinical psychologists—are involved in client counseling to encourage adherence.In Nigeria, there are designated health facilities that run daily retroviral clinics as well as provide free ART. This study was conducted in one of such facilities where PLWH are treated principally with two groups of drugs classified as “first line” and “second line”. The first line, which is the focus of this study, is presented as “combipak” containing three drugs—Zidovudine + Lamivudine + Nevirapine. The combination is administered one tablet each, twice daily. Patients are followed up on monthly appointments. In line with WHO's  revised However, it is often observed that some of these patients still fail to adhere to their treatment regimen. These patients return to the clinic for followup looking very ill with their drugs supply unexhausted. Various authors have observed that many PLWH do not adhere strictly to their treatment regimen , 9, 12, Various factors have been identified as posing challenges to adherence such as forgetfulness, side effects of the drugs, illiteracy, and stigmatization –14. In aA cross-sectional descriptive survey was conducted at the adult retroviral clinic of the Nnamdi Azikiwe University Teaching Hospital, Nnewi, southeast Nigeria. This centre is one of the designated free HIV retroviral outpatient clinics in the country. Two hundred and twenty-one adult HIV-infected patients were consecutively recruited into the study based on the inclusion criteria of: adult patients willing to participate and those who have been on ART for at least 3 months. Each patient that attended the ART outpatient clinic and who met the inclusion criteria was approached by one of the researchers; the purpose of the study, his/her role in the study, and the implication of his/her involvement were explained before a signed consent to participate was obtained.Nf = N/1 + (N)/(n), where N = Z2pq/d2 and n = estimated study population [The minimum sample size of 221 was determined using the statistical formula of Fisher for calculating sample size: pulation . AverageThe instrument used for this study was ART non-adherence and socio-demographic characteristics questionnaire (ARTNa-SDCQ) developed by the researchers based on the literature review. The questionnaire contained two sections. Section A was on sociodemographic data of respondents; section B contained four close-ended questions on: the duration of time a patient had been taking drugs; whether; ever missed drugs; how often drugs were missed and reasons for non-adherence . Adherence was defined in this study as having taken at least 95% of the total prescribed pills at the prescribed dosing intervals as recommended by WHO . This waThe reliability of the instrument was established by pilot testing it in an outstation ART clinic similar in characteristics to the study population. Twenty adult HIV-infected patients attending the ART clinic who met the study inclusion criteria were used. Data obtained were subjected to Cronbach's alpha test. An alpha of 0.72 and a standardized item (inter item) coefficient of 0.85 were obtained.The study was approved by the Research Ethical Committee of Nnamdi Azikiwe University Teaching Hospital, Nnewi, where the study was to be conducted. Permission was obtained from the management of the ARV clinic. Subsequently, each prospective respondent was approached by any of the researchers and the purpose and demands of the study were explained. They were informed that participation was voluntary and were assured of anonymity and confidentiality of information before informed consent was obtained.Copies of the questionnaire were administered directly to the consenting patients and left-over pills were counted by the researcher to corroborate patient's response. Any patient with more than 5% left over  of each drug was considered nonadhering. Data were collected on each clinic day before the routine clinic activities commenced. This was to reduce patients' distractions in form of going for CD4 count check and other laboratory investigations. The researchers assisted those who needed help to complete the questionnaire. Data collection continued on subsequent clinic days until the sample size was reached and this lasted for one month.t-test for unpaired data was used to analyze the relationship between respondents' adherence to ART and their demographic characteristics of sex and marital status, while analysis of variance (ANOVA) was employed to establish the relationship with their age, educational qualification, and employment status at P ≤ 0.05.Data collected on demographic characteristics and adherence to drugs were analyzed descriptively. Responses to factors responsible for non-adherence were categorized into three groups: client, institutional, and medication related factors. The relationship between respondents' demographic characteristic, and their reasons for non-adherence to drugs were analyzed inferentially using GraphPad Prism 5.20 statistical package. Of the 221 respondents, 188 (85.1%) indicated that they missed taking their drugs as prescribed in the preceding month while only 33 (14.9%) claimed they had never missed. Of the 188 patients that admitted non-adherence, 86 (45.7%) have been on ART for less than one year and 72 (38.3%) were on drugs between one year and 2.5 years, while the remaining 30 (16.0%) maintained the intake beyond 2.5 years and up to 5 years.tcal was 2.414 and P = 0.0213. The mean ± SEM of gender in relation to the factors was 25.22 ± 4.16 for the females and 14.39 ± 1.69 for the males. Except for forgetfulness, poor communication and side effects of drugs were identified by higher percentages of females than the males; more males than females identified the rest of the items.Out of the 188 patients on ART who indicated they had missed taking their drugs as prescribed in the preceding month, 126 (67.0%) were females while 62 (33.0%) were males see . The majF = 2.440 and P = 0.0973).There was no definite pattern in the responses based on age see . Howevert-test of the data at 95% CI and df = 34 showed tcal as 0.3948 and P = 0.6955. Overall, there was no significant difference in non-adherence factors identified by the married and single adult HIV-infected patients on ART.One hundred and seven (56.9%) of the respondents were married, while the remaining 81 (43.1%) were single . Many of the items had close responses from the groups see . HoweverF = 4.839 and P = 0.0041).The majority of the respondents had some formal education. Seventy-seven, 52, and 28 had secondary, higher and primary education, respectively, while 31 had none see . All catF = 9.525; P = 0.0003).Employed respondents 92 (48.9%) were more likely to miss their drugs when compared with the artisans 95 (29.3%) and unemployed groups 41 (21.8%). The rate of nonadherence to antiretroviral drugs among patients receiving ART in Nnamdi Azikiwe University Teaching Hospital, Nnewi, as shown in this study was rather high as only 14.9% (33) of the subjects indicated that they have never missed their medication. This is particularly significant considering that the method of data collection was self-report. Although previous studies had noted that some PLWH do not adhere strictly to their treatment regimen , 9 the rWith regard to gender and factors of non-adherence, it was noticed that more males than females were more likely to complain of factors like busy schedule, fear of partner disclosure, long waiting period, ignorance of consequences, long term regimen, and stigma. However, more females than males seemed to be non-adherent due to forgetfulness, poor communication, and side effects of drugs. These findings are not quite in agreement with those of Wasti et al.,  where woConcerning the relationship between non-adherence factors and age, the 40–49 years age group was the most nonadherent due to forgetfulness. Social responsibilities tend to increase with age and this may probably have been the case with this e eldest group in this study. Patients aged 20–29 years were most frequently nonadherent because they did not feel like taking drugs. The findings also interestingly showed that the same group reported ignorance of the consequences of their non-adherence more than the other two groups. However, statistical analysis did not show any significant variation in the factors of non-adherence as a result of age.There was also no significant difference in non-adherence factors between the married and the single respondents. This finding is not consistent with that of Agu et al.  and BellEducational status had a significant influence on some of the factors associated with non-adherence although no definite pattern was shown. Forgetfulness was common to all the categories. However, those with higher education were more likely than the other groups to attribute their non-adherence to busy schedule. Patients with no formal education were more likely to attribute non-adherence to poor communication, side effects of drugs, stigma, and lack of trust and confidentiality. Although Agu et al.  and BellThe results further showed that employed patients were more likely to cite forgetfulness, busy schedule, and stigma as reasons for non-adherence than the unemployed and artisans. This finding was statistically significant. The possible explanation is that their jobs kept them busy making them forget their drugs. Also the fact of working in an employed job may heighten their fear of stigma since they spend a good chunk of their time in the company of other people in their places of work; this may contribute to their forgetfulness. Stigma will not make them bring out their drugs in the office. Fear of stigma in the place of work may also be due to fear of losing their jobs if their HIV statuses are known.On the basis of the foregoing, in-depth one-on-one counseling will most likely help clients to resiliently withstand sigma, accept their condition, and adapt more positively to the challenges of the illness and prolonged drug use. Again, follow-up of patients on ART will most likely help to reduce factors of non adherence like forgetfulness, ignorance, and lack of confidence in treatment.Non-adherence was found to be high among the respondents in this study and several factors were cited as reasons. More information, education, and communication campaigns targeted at the general public are required to eliminate or reduce stigma to the barest minimum. This will help to improve adherence for those who might have the need to take their medications outside their homes, such as those in paid employments. Policies should be made and rules should be enforced to protect the rights of PLWH in the work place as well as prevent any form of discrimination against them. Health care providers need to spend sufficient time in adherence counseling at every visit emphasizing eating before drugs intake to minimize side effects. Strategies to automatically remind patients at due medication times such as setting alarms will be invaluable to reduce forgetfulness. Further studies are required to determine particular drugs which clients find most problematic.


Generalizable data are needed on the magnitude and determinants of adherence and virological suppression among patients on antiretroviral therapy (ART) in Africa.We conducted a cross-sectional survey with chart abstraction, patient interviews and site assessments in a nationally representative sample of adults on ART for 6, 12 and 18 months at 20 sites in Rwanda. Adherence was assessed using 3- and 30-day patient recall. A systematically selected sub-sample had viral load (VL) measurements. Multivariable logistic regression examined predictors of non-perfect (<100%) 30-day adherence and detectable VL (>40 copies/ml).Overall, 1,417 adults were interviewed and 837 had VL measures. Ninety-four percent and 78% reported perfect adherence for the last 3 and 30 days, respectively. Eighty-three percent had undetectable VL. In adjusted models, characteristics independently associated with higher odds of non-perfect 30-day adherence were: being on ART for 18 months (vs. 6 months); younger age; reporting severe (vs. no or few) side effects in the prior 30 days; having no documentation of CD4 cell count at ART initiation (vs. having a CD4 cell count of <200 cells/µL); alcohol use; and attending sites which initiated ART services in 2003–2004 and 2005 (vs. 2006–2007); sites with ≥600 (vs. <600 patients) on ART; or sites with peer educators. Participation in an association for people living with HIV/AIDS; and receiving care at sites which regularly conduct home-visits were independently associated with lower odds of non-adherence. Higher odds of having a detectable VL were observed among patients at sites with peer educators. Being female; participating in an association for PLWHA; and using a reminder tool were independently associated with lower odds of having detectable VL.High levels of adherence and viral suppression were observed in the Rwandan national ART program, and associated with potentially modifiable factors. In recent years, HIV care and treatment programs in sub-Saharan Africa have shifted from an emergency response with a focus on quickly initiating the sickest HIV-infected patients on antiretroviral therapy (ART) to building sustainable programs which provide lifelong treatment to very large numbers of patients across the HIV disease spectrum. Among the pillars of sustainable HIV treatment programs is the ability of patients to achieve and maintain adequate adherence to ART for life. Adherence is critical for improving the patient’s own prognosis In contrast to the growing literature on levels and determinants of patient retention from nationally representative or large multi-site samples of ART patients in Africa Rwanda has an estimated adult national HIV prevalence of 3% (2% in men and 4% in women) By the end of February 2007, approximately 18 months prior to study start, 113 health facilities, including 79 public facilities and 34 faith-based facilities, were providing ART, and according to the national monitoring and evaluation system, 9,693 adults were on ART: 3,628 for 6 months 3,086 for 12 months, and 2,979 for 18 months. From September 2008 to April 2009, we conducted a cross-sectional study in 20 of the 113 facilities.Sample size calculations were based on the expected proportion of patients reporting perfect adherence 18 months after ART initiation as that proportion was expected to be lower than those at 6 and 12 months after ART initiation. Assuming an 18-month perfect adherence rate of 85%, a precision of ±5% or less, a design effect of 1.5, and a refusal rate of 25%, as well as application of a finite population correction factor and logistical considerations, a sample of 1,798 patients spread across 20 sites was considered adequate.Study participation was restricted to adults aged ≥18 years at study enrolment who had initiated first-line ART at one of the study sites 6, 12 and 18 months [+/−2 months] prior to data collection and were still receiving treatment at their initiating site, or transferred into one of the study sites within 30 days of ART initiation and were still receiving it at that site. Patients who died, were lost to follow-up , transferred to another clinic before study start were excluded, as were those who continued in care at their initiating site but had stopped ART prior to data collection.Stratified multi-stage cluster sampling was used, with sites as clusters, and six strata according to type of facility (public and faith-based) and time on ART . The first stage of sampling involved randomly selecting 14 public and 6 faith-based sites from the 113 sites providing ART services 18 months prior to study start, with the total number of each type of site determined based on the relative contribution of each of those types of sites to the total number of adults on ART in Rwanda recorded in the national monitoring and evaluation system. In the second stage of sampling, patient registers and charts at the selected sites were used to create sampling frames of all eligible patients per strata. The desired sample size per strata was determined based on the relative contribution of eligible patients in each stratum to the total number of eligible patients identified. The sample per strata was divided across sites based on the relative contribution of eligible patients at each site to the total number of patients required per strata. Potential participants were selected from the site-specific sampling frames using simple random sampling. Individual records were reviewed for each potential participant selected using random sampling to confirm that they met the study eligibility criteria. If a patient was found to be ineligible, she or he was replaced by another eligible patient from the appropriate site-specific sampling frame using a random replacement scheme.Site staff otherwise unaffiliated with the study contacted the selected patients confirmed to meet the study eligibility criteria at home and invited them to return to the health facility to learn more about the study. For patients who presented to the clinic, study staff provided more details about the study, obtained written informed consent, and completed interviews. Every alternate participant was included in the viral load sub-sample, with blood draw occurring immediately after the interview. Participants received the equivalent of US $4.50 to cover transport to the clinic to participate in the study. Patients who did not present to the facility following the invitation by the site staff, refused to participate after presenting to the facility, or could not be located were not replaced.Trained interviewers conducted face-to-face interviews which lasted approximately 45 minutes using a closed-ended questionnaire translated into Kinyarwanda. The questionnaire covered socio-demographic characteristics, psychosocial support, ART-related side effects, health behaviors and beliefs. Adherence was measured by patient recall of the number or percentage of doses taken during the three and 30 days prior to interview. Specifically, three-day patient recall was assessed using questions developed by the Adult AIDS Clinical Trials Group which have been previously validated in the United States Interviewers used a structured tool to abstract data on ART regimens, clinic visits and CD4, weight and WHO stage assessments since enrollment into care from patient medical charts and pharmacy records.For patients selected into the viral load sub-sample, blood specimens were collected by the site phlebotomist in PPT or EDTA tubes . Depending on the distance of the site from the National Reference Lab (NRL) in Kigali, samples were either transported directly to the NRL for centrifuging within four hours of being drawn, or centrifuged at the site or a nearby District Hospital within four hours and then transported to the NRL within 18 hours. Plasma levels of HIV RNA were quantified by real-time PCR using a Cobas TaqMan 48 machine  with a detection limit of 40 RNA copies/mL.Data on facility- and program-level factors that may impact adherence at the patient level were obtained for each site. Interviewers completed a structured assessment tool via discussion with the director of the facility or the HIV clinic, or another staff member familiar with the day-to-day operations of the HIV clinic.th and 75th percentile cut-offs, representing whether the respondent experienced no or few side effects, moderate side effects or severe side effects. If CD4 counts were not available from the visit at which ART was initiated, results from up to three months before or after the date of ART initiation were used.Data were double data entered into a Questionnaire Design Software (QDS™)  database and analyzed using survey procedures in SAS Version 9.2  designed for complex survey data. Sampling weights accounting for the probability that a site would be selected from the 113 in the sampling frame (by type of site: public and faith-based) and the probability that a patient would be selected from the site-specific sampling frame of all patients on ART  were used together with finite population correction factors in all analyses to obtain nationally representative estimates. Descriptive statistics were used to describe study sites and patient characteristics by time since ART initiation. Principal components analysis considering information on dwelling conditions and household assets was used to create a poverty index which was then divided into tertiles, representing the poorest, middle and least poor respondents. An index of side effects was generated by summing scaled responses to whether each of 19 side effects were experienced and if so, their severity, in the 30 days prior to interview; the index was categorized based on the 25Primary outcome measures were three-day adherence, 30-day adherence, treatment interruptions, and viral load at the time of interview. Adherence and viral load were treated both continuously and categorically using clinically relevant thresholds. Treatment interruptions were examined using rates per person-year on ART. The four measures were compared across time since ART initiation strata using descriptive statistics, as appropriate. Logistic regression analysis was used to identify patient- and site-level characteristics associated with two of those outcomes: sub-optimal 30-day adherence and detectable viral load. Sub-optimal adherence was defined as patient report of having taken less than 100% of prescribed doses in the 30 days prior to interview, and viral loads of more than 40 copies/mL were designated as detectable. Non-collinear factors significant at the α≤0.2 level in unadjusted models were introduced in multivariable models. Variables that were statistically significant at α≤0.05 and that contributed to the overall goodness of fit of the model were retained in the final models. If not independently associated with the outcome, time since ART initiation, age, sex and CD4 at ART initiation were forced into the final models regardless of their statistical significance. Characteristics associated with three-day adherence and treatment interruptions were not assessed due to insufficient variability in the data.The study protocol was approved by the National AIDS Commission, the National Ethics Committee and the National Institute of Statistics in Rwanda, as well as by the Institutional Review Board at Columbia University. All participants provided written informed consent prior to interview, and when applicable, prior to blood draw for viral load assessment.According to government data, a total of 1,951 patients were believed to have started ART 6, 12 and 18 months prior to data collection at the 20 study sites, 1,798 (92%) of whom were randomly selected for inclusion in the study. Of those selected for inclusion, 1,472 (82%) were confirmed to meet the study eligibility criteria following individual record review, and 1,417 (96%) of those patients could be located and agreed to participate, including 571 (40%), 491 (35%) and 355 (25%) who started ART 6, 12 and 18 months prior to data collection, respectively. A total of 837 (59%) of the 1,417 participants received viral load assessments, including 331 (40%) who had been on ART for 6 months, 284 (34%) on for 12 months and 222 (27%) on for 18 months . After aOf the 20 study sites, 14 (70%) were public sector and six (30%) were faith-based, as per the study design. Eleven (55%) were located in rural areas. There were 14 (70%) primary-level health centers and six (30%) secondary-level hospitals. Seven (35%) sites had started providing ART services in 2003 or 2004, seven (35%) in 2005 and six (30%) in 2006 or 2007. Six (30%) sites had active peer educator programs and ten (53%) conducted routine home visits for patients.As shown in In adjusted models controlling for duration on ART, age and CD4 count at ART initiation, higher odds of having a detectable VL were observed among patients at sites with peer educators . Being female ; participating in an association for people living with HIV/AIDS ; and using a reminder tool  were negatively associated with having a viral load of more than 40 copies/mL.As the first nationally representative study on adherence, treatment interruptions and viral suppression among patients on ART in sub-Saharan Africa, this study provides important insights on program outcomes previously not sufficiently described in the context of rapid scale-up of HIV services. Additionally, as Rwanda is one of the small handful of countries in sub-Saharan Africa that has achieved universal treatment coverage, we were able to assess whether program quality can be maintained as countries reach that goal. Reassuringly, very high program quality was observed. Overall, across the population on ART for 6, 12 and 18 months in Rwanda, 94% reported perfect three-day adherence and 78% reported perfect 30-day adherence. This finding is consistent with that reported in smaller studies in East Africa A number of patient characteristics were associated with higher odds of non-adherence, including longer time on ART, younger age, experiencing severe side effects, not having a CD4 count at ART initiation, and alcohol use. Patients who had been on ART for 18 months had 75% higher odds of non-adherence compared to those who had been on ART for 6 months. This trend was also observed among adults in a South Africa Several patient characteristics were also independently associated with lower odds of non-adherence and having a detectable viral load, and suggest avenues for intervention among patients experiencing adherence problems. Indeed, participation in a PLWHA association, which we found to be associated with decreased risk of non-adherence and having a detectable viral load, may encourage positive behaviour among patients on ART. Additionally, while use of reminder tools was not associated with self-reported adherence, their use was significantly associated with low odds of having a detectable viral load, providing further evidence that they promote adherence Significant variability by site was observed in all study outcomes, suggesting opportunities exist for site-level interventions to optimize outcomes. Patients attending high volume sites had higher odds of non-adherence probably due to insufficient staff time to focus on this aspect of patient management. Patients attending sites that had started implementation of ART services earlier in scale-up also had higher odds of non-adherence than those attending less mature sites. More research is needed to understand this finding, including assessing the contribution of health worker fatigue. Such sites might benefit from implementing supportive home visits, which were associated with reduced odds of non-adherence in our study. In contrast, we found that patients attending sites with peer educator programs had higher odds of non-adherence and of having a detectable viral load. While some studies suggest that peer support is associated with better adherence, particularly if it includes implementation of directly observed therapy Our study has several important strengths. To our knowledge, it is the first nationally representative assessment of adherence, viral suppression, and treatment interruptions among patients on ART in Africa and possibly worldwide. Having both patient-level and site-level data allowed us to explore a wide range of correlates of optimal adherence and viral suppression. A few limitations should be noted, however. While the objective of our study was to assess outcomes among patients who remained on treatment for 6, 12 and 18 months, it is likely that those who were not retained had worse adherence and more treatment interruptions, and thus were less likely to achieve viral suppression. Similarly, while non-participation was extremely rare and restricted to 55 (3.7%) of patients confirmed to be eligible for the study, these patients likely had worse outcomes than study participants; indeed, assuming all such patients had non-perfect adherence and detectable viral loads, the overall weighted proportion of participants with perfect 3-day and 30-day adherence, and undetectable viral load would be 90%, 74%, and 78%, respectively. Additionally, lack of variation in some site-level variables precluded their inclusion in multivariable models. Finally, due to financial constraints, we were unable to perform viral load assessments for all patients which limited our power to detect significant associations when modelling predictors of detectable viral load.In conclusion, high levels of self-reported adherence and virological suppression, and low rates of treatment interruption were observed among a nationally representative sample of patients on ART for 6, 12 and 18 months in the Rwandan national program. Our results suggest that strategies to maximize adherence in these settings should include reminder tools, alcohol screening and treatment, participation in PLWHA associations and supportive home visits.


Challenges to HIV care in resource limited settings (RLS) include malnutrition. Limited evidence supports the benefit of nutritional supplementation when starting antiretroviral therapy (ART) in RLS.Randomized controlled pilot study. HIV-positive ART-naive adults with self-reported weight loss were randomized to receive ART plus FutureLife porridge® nutritional supplement (NS)  or ART alone (Controls) for 6 months. Patients returned for monthly assessments and blood was drawn at enrolment and 6 months on ART. Differences in body composition, biochemical and laboratory parameters were estimated at 6 months on treatment.3 [IQR 12–105 vs 107 cells/mm3 [IQR 63–165]; p = 0.149) and hemoglobin .Of the 36 randomized patients, 26 completed the 6 month follow-up (11 NS vs 15 Controls). At enrolment, groups were similar in terms of age, gender, body mass index (BMI) and bioelectrical impedance. NS patients had a lower median CD4 count (60 cells/mm3 [IQR 120–174) vs 77 cells/mm3 [IQR 33–145] in the Controls. NS patients had higher mean percentage change in body weight , BMI , absolute CD4 count  and hemoglobin . Patients in the NS arm had a higher mean percentage fat-free mass , total body water , intracellular water  and basal metabolic rate  compared to Controls. Patients in the NS arm also showed an improvement in physical activity at 6 months post-ART initiation compared to Controls (p = 0.037).At 6 months, NS patients increased their median CD4 count by 151 cells/mmPreliminary results are encouraging and suggest that NS taken concurrently with ART can promote weight gain, improve immune response and improve physical activity in HIV-positive patients that present at ART initiation with weight loss. Malnutrition is a significant factor affecting human immunodeficiency virus (HIV) care and treatment in resource limited settings and contributes to other infections, including tuberculosis ,2. IndivAdequate diet is believed to be important for adherence to antiretroviral therapy (ART) as inadequate nutrient intake is known to favour opportunistic infections and contributes to wasting. Individuals with HIV/AIDS require greater protein and micronutrient intake to support a weakened immune system  however 2) [Lack of essential micronutrients may not only contribute to the depletion and dysfunction of CD4 cells but malnourished patients may have a suboptimal response to treatment when (ART) is initiated . Studies2) .The benefits of ART on HIV-related survival are well-described and studies have shown that ART improves body mass index – a proxy for nutritional status -14. Once+ lymphocyte count < 200 cells/mm3) [A variety of assessment tools can be used to determine nutritional status; these include anthropometric methods (i.e. skinfold measurement and mid-upper-arm circumference), BMI and bioelectrical impedance analysis (BIA). BIA allows researchers to determine the specific component of weight loss  that is biologically relevant to the development of adverse outcomes. BCM refers to the cellular and metabolically active components of the body, including muscles, solid organs and intracellular water while FFM includes all the components of BCM plus additional components that are not metabolically active (extracellular water and tissue support) . BIA is Nutritional supplementation has been shown to boost overall health and energy, provide immune system support, increase efficacy of other medical treatment, improve general quality of life and support the healing process ,23. NutrWe hypothesized that supplementation with additional calories and protein would improve nutritional status and possibly have an effect on body weight and immune status of HIV-positive patients starting ART. We investigate the effect of a nutritional supplement taken concurrently with ART for 6 months on body mass index and body composition as well as on laboratory and biochemical markers.We conducted a randomized controlled pilot study at the Themba Lethu HIV Clinic at the Helen Joseph Hospital, a public-sector hospital in Johannesburg, South Africa between May 2010 and November 2011. This cohort has been described previously . The pilForty-five antiretroviral naïve patients were recruited on the day they initiated standard first-line antiretroviral therapy (ART) according to the South African National Department of Health ART treatment guidelines . PatientFollowing patient screening and informed consent, study subjects were randomized 1:1 in permuted blocks of five to receive either ART plus FutureLife porridge®  (NS) or ART alone (Control) for 6 months. Participants in the intervention arm were provided with, and instructed to consume, a high-protein high-energy meal , divided into several servings, concurrently with ART for 6 months , opportunistic infections and WHO stage were retrieved from the site’s electronic patient management system, TherapyEdge-HIV™. Laboratory data including CD4 count, hemoglobin and mean cell volume (MCV) at 12 months after ART initiation was also obtained from TherapyEdge-HIV™. All patients signed informed consent to take part in the study which, together with the use of TherapyEdge-HIV™ data, was approved by the University of the Witwatersrand Human Research Ethics Committee .Blood samples were taken at enrolment and again at 6 months on treatment and included CD4 cell count, HIV-RNA viral load, MCV, hemoglobin, red blood cell, white blood cell and platelet count. Biochemical measurements included alanine transaminase (ALT), serum albumin, pre-albumin, iron (Fe), ferritin, % transferrin saturation, folate, magnesium (Mg), selenium and total calcium. Urine samples were collected at each visit for urine urea, creatinine and protein to monitor kidney function.Height and weight together with bioelectrical impedance was collected for each patient at each monthly visit for 6 months. BMI, body fat percentage (% fat), FFM, lean dry mass (LDM), total body water (TBW), intra- and extra-cellular water , phase angle α, basal metabolic rate  and daily energy expenditure (DEE) were estimated using the RJL Body Composition 2.1 software from the resistance, reactance and patient details that were recorded .Physical activity was assessed at enrolment, 3 months and again at 6 months using a physical activity recall questionnaire. This included 16 multiple choice questions to assess an individual’s level of activity and calculate a physical activity score. In addition a 5 day physical activity recall diary using activity codes  and pedo3). In addition, we assessed patient outcomes and changes in CD4 count, hemoglobin and MCV from ART initiation until 12 months after ART initiation, by treatment arm using data from TherapyEdge-HIV™). Patients were followed until the end of the study period (completers) but patients that prematurely discontinued study treatment (non-completers)  were excluded from the final analysis. Data was analyzed using SAS 9.3 . A p value < 0.05 was considered significant in all analyses.Patient demographics and clinical characteristics at ART initiation (baseline) were summarized and compared using T-test or Kruskal-Wallis for continuous data and Chi-square test for proportions. Results were presented using proportions or medians with interquartile ranges. Changes in body weight, BMI, bioelectrical impedance and biochemical, clinical and laboratory markers from ART initiation until 6 months follow-up were compared, by treatment arm, using paired T-test or Wilcoxon rank sum test for continuous data. Analyses were also adjusted for baseline CD4 cell count, hemoglobin, viral load, sex and age using repeated-measures analysis of variance (rANOVA). Changes in BIA and physical activity parameters were also stratified by level of immunodeficiency at study entry . Of the 7 patients that were not randomized, 1 patient did not have a valid SA ID document, 1 patient was admitted to hospital before he could be randomized and 5 patients did not return to the clinic.Twenty six patients completed the 6 month follow-up visit (11 NS arm and 15 Control arm). On the NS arm, 3 patients transferred out, 3 patients withdrew from the study and 2 patients died. On the Control arm, 1 patient was LTFU, 1 patient transferred out and 2 patients withdrew from the study. The main reason for withdrawing from the study was work commitments (i.e. security guard on night shift). Non-completers were no different from completers in terms of age, gender or baseline BMI, hemoglobin, CD4 count and viral load , though more non-completers were initiated on TDF/3TC/NVP or d4T/3TC/EFV (p = 0.031) , lower median hemoglobin  and higher median body mass index  compared to those in the Control arm. A greater proportion of patients in the NS arm had a CD4 ≤ 50 cells/mm3  together with a current or prior history of alcohol use (p = 0.029). Patients in the NS arm had higher physical activity scores at treatment initiation than those in the Control arm . The score is the inverse of the physical activity so patients in the NS arm had a higher score but lower physical activity compared to the Control arm.Patients in the NS arm were similar to those in the control arm in terms of age, gender, education and employment Table . Patient3 at 6 months (p = 0.048). Likewise, patients in the NS arm increased their CD4 count by 151 cells/mm3 vs. 77 cells/mm3 in the Control arm (p = 0.024).At 6 months on ART, patients in the NS arm demonstrated a greater increase in weight , BMI , CD4 count  and hemoglobin  when compared to Controls  and white blood cells  when compared to the Control arm. Serum ferritin was the only biochemical marker that showed a significant change between the two arms, patients in the NS arm had a decrease in serum ferritin compared to the Control arm .In analyses adjusted for baseline CD4 cell count, haemoglobin, viral load, sex and age, the supplement group showed significant increases in weight (p = 0.054), BMI (p = 0.028), CD4 (p = 0.002), hemoglobin (p = 0.053), white blood cells (p = 0.051) and red blood cells (p = 0.015).3 showed a significant increase in FFM (p = 0.025), ICW (p = 0.016), ECW (p = 0.015) and BMR (p = 0.040) , TBW , ICW , ECW  and BMR  were all higher in the NS arm compared to the Control arm. These results were confirmed in a sub-analysis where only patients in the NS arm with a CD4 count ≥ 100 cells/mm3) showed a significant improvement in physical activity (p = 0.028) . In a sub-analysis, only patients with baseline immunodeficiency , weight  and appetite  compared to those in the Control arm. The nutritional supplement did not significantly contribute to adverse side effects in terms of depression , body pain or headaches , nausea , fever , skin rashes , stomach cramping , vomiting or diarrhoea , bloating or flatulence  or insomnia . During the course of the study, 2 patients were diagnosed with Herpes zoster  while 1 patient on the NS arm was diagnosed with peripheral neuropathy on tenofovir with lamivudine and efavirenz.Tolerance of, and adherence to, the NS was good during the study period. 82% (9/11) of patients in the NS arm reported taking the supplement every day for the previous month. Patients on both the NS arm  and the Control arm  reported good ART adherence .Twenty patients were still alive and in care 12 months after ART initiation (9 NS arm and 11 Control arm). On the NS arm, 1 patient transferred out (196 days) and a second was LTFU (428 days). On the Control arm, 2 patients transferred out (median 393 days IQR 372 – 415) and 2 patients were LTFU (median 416 days IQR 378 – 454).The difference in CD4 count increase between the two arms observed at 6 months did not continue after the completion of the study, where the supplement was stopped and both arms continued on ART alone. The % change between 6 and 12 months after ART initiation was 41.6% (IQR 36.9 – 97.0) for the NS arm and 31.5% (IQR −15.7 – 54.2) for the Control arm (p = 0.309). However the difference in BMI increase between the two arms was still evident 12 months after ART initiation, even after patients on the NS arm had stopped taking the supplement. The % increase at 12 months was 4.2% (IQR 3.9 – 12.0) for the NS arm compared to 0.2% (IQR −15.7 – 54.2) on the Control arm (p = 0.046).Adequate nutritional status supports immunity and physical performance . Weight 3 at study entry.We demonstrate that nutritional supplementation taken concurrently with ART for 6 months resulted in an increase in BMI, CD4 count, hemoglobin, red blood cell and white blood cell count and improvement in physical activity when compared to Controls. In addition, serum ferritin was the only biochemical marker that was significantly different between the two arms. Patients in the NS arm showed an increase in FFM, TBW, ICW, ECW and BMR when compared to Controls. Phase angle α was also higher in patients in the NS arm  which may suggest improved health in these patients which may result in improved treatment outcomes. By 12 months after ART initiation, patients in the NS arm continued to show a significant increase in BMI but not CD4 count when compared to the Control arm. The greatest gain in CD4 count and improvement in physical activity was observed in patients in the NS arm with a CD4 count < 100 cells/mmBaseline characteristics between the NS and the Control arm were similar although patients in the NS arm were slightly older with a lower CD4 count and hemoglobin. These patients also had a lower viral load, higher BMI and a greater improvement in physical activity level compared to those in the Control arm. These differences are likely due to chance and not the incorrect randomization of sicker or thinner patients to the NS arm.6 cells/L IQR 10 - 85) in their study using a multivitamin supplementation [We observed an improvement in various parameters in the intervention arm. Patients in the NS arm demonstrated an increase in body weight, BMI, CD4 count and hemoglobin. These results suggest that nutritional supplementation for 6 months led to an improved recovery of the immune system and an improvement in the body’s ability to fight infections. This also supports reports that adequate nutrition promotes and maintains optimal immune function . Fawzi aentation ,31,32 whentation .Studies have reported that ART improves BMI while nutritional supplementation further increases BMI ,27,34,35The effect of a specific micronutrient will depend not only on the background intake of the micronutrient given, but also on the intake of other interacting micronutrients. To assume that all study participants are initially deficient with respect to one or more micronutrients would be incorrect . Serum fSignificant increases in FFM, TBW, ICW and ECW were observed in the supplement arm compared to the Control arm, findings similar to those reported by Swaminathan and colleagues (2010) and Schwenk and colleagues (1999) ,39. The 3 have lower median values for bioelectrical impedance at ART initiation [3. Swaminathan and colleagues (2010) found that gains were greater in patients with CD4 cell counts < 200cells/mm3. A possible explanation for the lack of effect seen in severely immunosuppressed patients (CD4 < 100 cells/mm3) may be that ART needs to be established first before malnutrition can be treated or before protein synthesis and immune-related enzyme systems can resume their functions [3) in the intervention arm showed the greatest improvement in physical activity.As expected, and consistent with other reports, patients with a CD4 count < 100 cells/mmitiation . Reportsitiation . Howeverunctions . As prevunctions . Interes2. Our results suggest that patients in the NS arm are more likely to be in care by 6 months after ART initiation compared to the Control arm, who were provided standard of care (Hazard ratio 1.26 95% CI 0.65 – 2.42), however this was not statistically significant and our study had insufficient statistical power to demonstrate this difference. Of concern, are the high rates of loss to initiation and LTFU, both common problems in resource limited settings.This is one of a few studies investigating a nutritional supplement intervention that compares attrition across 2 groups of HIV-positive patients. Long term follow-up provided the opportunity to comment on patient outcomes 6 months after the completion of the study (12 months after ART initiation). Very few studies have assessed the impact of food supplements or reported on mortality, morbidity or disease progression ,23. OnlyThe supplement was well tolerated, as evidenced by the absence of gastrointestinal symptoms and adverse side effects in the nutritional supplement arm. This may have provided an incentive for regular clinic attendance. An adequate diet is an important factor influencing adherence to ART . Studies2) but also HIV-positive patients that present at ART initiation with self-reported weight loss. Second, as Sattler and colleagues (2009) highlighted, it is important to obtain weight and dietary history and quantification of total energy and macronutrient intakes  before prescribing nutritional supplements for patients with HIV [Our finding should be considered in light of the study limitations. First, our results may also be biased by the number of patients who were excluded in the first days and weeks of the study mainly lost to initiation, sicker patients who required hospitalization, disinterest in the intervention or patients that transferred out or withdrew due to work commitments. Both arms presented equally with self-reported weight-loss and advanced HIV disease. Our findings are not only applicable to malnourished HIV-positive patients  and improving physical activity, thereby improving quality of life and ultimately reducing HIV-associated complications. Larger studies with long-term follow-up are necessary to validate these data.The authors have declared that no competing interests exist. Right to Care (RTC) provided some of the funding for the current research and also supports the provision of treatment for the patients in the study.IS, MM and DE contributed to study design, implementation of the study and supervised data collection. LM performed data management. DE performed statistical analysis and wrote the first draft of the manuscript. TW, KS, DvA, NB assisted with the design of study, facilitated the implementation of the study, responsible for data collection and verification and also provided patient care to study participants. IS, MM, DE and LM critically reviewed and revised the manuscript. The final version of the paper was reviewed and approved by all authors. All authors read and approved the final manuscript.