Introduction: Pharmacy adherence measures such as pharmacy dispensing ratios (PDRs) have previously been shown to be predictive of virologic outcomes. We aimed to determine the optimal interval of PDR assessment for predicting virologic failure for HIV-infected patients on antiretroviral therapy (ART).Methods: Using national Brazilian ART pharmacy refill data, we examined PDRs for patients ≥18 years of age with at least one HIV RNA level ≥180 days after ART initiation on or after 1 January 2011. Patients with a documented ART change ≤270 days prior to viral load test date were excluded. Logistic regression models were used to describe associations between virologic failure, defined as an HIV RNA level ≥400 copies/mL and PDRs, defined as the number of days index drug dispensed (non-nucleoside reverse-transcriptase inhibitor or protease inhibitor) per 180- and 90-day, interval preceding viral load testing, adjusting for sex, age, race, time since ART initiation and index drug. Backward elimination of insignificant variables was performed after adjusting for PDR. A predictive probability of virologic failure was calculated using the corresponding odds ratios for the PDR and any other significant variables. The diagnostic performance of the PDR interval was assessed by calculating the area under the receiver operating characteristic curve (AUROC) for the predictive probability with respect to virologic failure.Results and Discussion: A total of 1,025 patients were included . The PDR was found to be significantly associated with virologic failure for all of the PDR intervals (p < 0.001). There was an increased risk of virologic failure for all PDRs <0.95. The 90–180 days interval had a AUROC of 0.842, compared to 0.841 and 0.829 for the 0–180 days and 0–90 days intervals, respectively. The PDR performed well as a predictive tool to identify patients in virologic failure with the 90–180-days interval prior to viral load testing being marginally more predictive.Conclusions: The validation and use of the pharmacy dispensing ratio using public pharmacy refill data could aid in early identification of patients with poor adherence and prevent development of treatment failure and drug resistance in Brazil. The ability to achieve and maintain viral load suppression for human immunodeficiency virus (HIV)-infected patients on antiretroviral therapy (ART) is dependent on, among other factors, a high level of adherence to the drug regimen –3. SubopGiven the importance of adherence to ART in patient outcomes, various methodologies exist for assessing levels of adherence to ART, including patient self-report, pharmacy-based measures, pill-counts, and biological markers . PatientStudies have demonstrated the association of various measures of adherence and plasma HIV RNA levels ,11,12. IWe conducted a cross-sectional study using data obtained from the longitudinal, clinical database of HIV-infected patients receiving care at the Instituto de Pesquisa Clinica Evandro Chagas (IPEC) in Rio de Janeiro, Brazil. IPEC has been providing care to HIV-infected patients since 1986. The clinical database was established in 1998 and has since been updated regularly using outpatient and inpatient medical records, and laboratory results. Pharmacy prescription pickup data were obtained from the national Brazilian ART pharmacy control system. That database contains information regarding drug regimen, number of days' supply of medication dispensed, regimen changes and justification for drug regimen changes for all patients enrolled in the National HIV/AIDS Programme.Patients greater than or equal to 18 years of age with at least one HIV RNA level occurring from 1 January 2011 through 31 December 2011 greater than or equal to 180 days after ART initiation to allow time for virologic response to treatment were included in the analysis. Patients with a documented regimen change less than or equal to 270 days prior to viral load test date were excluded to ensure patients were on a stable regimen at time of viral load testing and to allow for virologic response to treatment changes.The first HIV RNA viral load test occurring greater than or equal 180 days after ART initiation occurring from 1 January 2011 through 31 December 2011 was analyzed for all patients. The outcome of interest was virologic failure, defined as ≥400 copies/mL, to account for less sensitive virus detection thresholds of older testing platforms.The PDR was calculated based on the number of days’ supply of index drug dispensed per 180-, and 90-day intervals preceding the viral load test date. A total of three assessment intervals were included; 0–180 days, 90–180 days and 0–90 days. Periods shorter than 90 days were not considered given that patients are generally required to pick up ARVs on a monthly basis. The index drug was defined as the non-backbone ARV included in the drug regimen, consisting of either a non-nucleoside reverse-transcriptase inhibitor (NNRTI) or protease inhibitor (PI). The decision to include only NNRTI- or PI-based regimens was based on prior data showing 90% of patients in treatment in 2011 were either on an NNRTI or PI based regimen . No distAdjusted logistic regression models were used to describe the association between virologic failure and PDR for each of the 180- and 90-day assessment intervals. The PDR was treated as a categorical variable according to the following thresholds, >0.95 or ≤0.95, which were based on prior studies citing increase likelihood of virologic failure in patients with ≤95% adherence . AdditioThis study was approved by the ethics committee of the Evandro Chagas Clinical Research Institute of the Oswaldo Cruz Foundation (CAAE 0032.0.009.000–10). Written informed consent for enrolment in the cohort was obtained from all patients. Retrospective analysis of previously collected data delinked from personal identifying information was considered exempt by the Columbia and University of California Los Angeles IRBs.A total of 1,025 patients were included in the analysis of which 68% were male with a median age [interquartile range (IQR)] of 40 years  and median time since ART initiation of 3.4 years  of which 57% were on an NNRTI. Less than 33% of patients had a PDR >0.95 . The medThe PDR was found to be significantly associated with virologic failure for all of the PDR intervals . There wAll of the PDR assessment intervals were found to have statistically significant AUROC. The 90–180 days interval was marginally superior at predicting virologic failure. In our observational clinical cohort, the PDR performed well as a predictive tool to identify patients in virologic failure. Our results are consistent with prior studies which demonstrate that the PDR can be used as a predictor of virologic failure and that upstream measures of adherence (>90 days prior to test date) are better predictors of virologic failure than more recent measures ,14. The We acknowledge that the sensitivities and specificities obtained are not sufficient to replace the need for viral load monitoring. However, our results demonstrate the possibility of developing a cost-effective predictive tool that could be used at the national, regional or district level by public health authorities to identify patients at highest risk of virologic failure, in settings where the cost of more expensive strategies such as pill counts and biological markers are prohibitive.Sex, age and time since ART initiation were not significantly associated with virologic failure after adjusting for PDR. Non-White race was found to be associated with an increased risk of virologic failure. This difference may potentially be explained by other factors not assessed within our model such as education and socioeconomic status, which may be correlated with race. A recent study within our cohort did not find race to be significantly associated with the odds of achieving virologic suppression; however, the prior study also adjusted for educational level, which was found to be significant factor .Index drug was significantly associated with virologic failure and patients on PI- versus NNRTI-based regimens were more likely to be in virologic failure. We did not distinguish patients based on first- or second-line regimen, however, based on the 2008 National HIV/AIDS Program treatment guidelines, NNRTI-based regimens are the preferred first-line regimen and lopinavir/ritonavir is preferred over atazanavir as the second-line PI . MoreoveThe generalizability of our study is limited because we derived the predictive model using only one cohort population. In order to validate further the national use of this predictive model, we would need to replicate our model using other patient databases within the national Brazilian ART pharmacy control system. Perhaps the greatest limitation of our study was the statistical programming required for the derivation of the predictive probability, which limits the ability to apply this tool to day-to-day clinical practice. However, the model could also be used as a surveillance tool by public health authorities to identify the geographic areas with the highest number of patients at risk of virologic failure, in order to implement targeted adherence interventions at the community level. In an effort to simplify the model, we calculated the PDR based solely on the index drug under the assumption that this would be a reliable proxy for overall adherence to therapy. We selected a threshold of >95% for the categorization of the PDR variable based on prior evidence supporting the use of this threshold; however, the median PDR for all intervals was only 0.75. Future research should evaluate lower PDR thresholds to determine if there is an optimal threshold for predicting virologic failure.In conclusion, we demonstrated the use of a predictive probability tool based on PDR and index drug for determining the likelihood of virologic failure at a future point in time for varying intervals of assessment. The validation and use of this predictive tool using pharmacy refill data available through the national Brazilian ART pharmacy control system could be of great benefit in early identification of patients with poor adherence and prevent development of treatment failure and drug resistance in Brazil. Following validation of these results, this tool could be applied at the national level in Brazil, and potentially other countries, to identify and further develop targeted adherence interventions in the geographic areas with the highest number of patients at risk of virologic failure. Additionally, further efforts should be made to explore the feasibility of designing a software program within the national Brazilian ART pharmacy control system that would automatize the calculation of the PDR and apply the predictive model on an ongoing basis, such that the system would automatically flag patients at highest risk of clinically significant non-adherence, thereby allowing clinical personnel to proactively intervene with targeted adherence interventions.


Changes in combination antiretroviral therapy (cART) throughout childhood challenge the continuity of paediatric HIV treatment. This study aimed to evaluate the prevalence of treatment interruption (TI), including lamivudine (3TC) monotherapy, and the relationship of TI to virologic and immunologic parameters in HIV-infected paediatric patients.Nested within a prospective observational study of a city-wide cohort of HIV-infected persons in the District of Columbia, this sub-study collected retrospective data on antiretroviral therapy, enrolment (endpoint) and historic (lifelong) CD4 counts and HIV RNA viral load (VL) of the paediatric cohort. TI was defined as interruption of cART ≥4 consecutive weeks. Data on TI, including 3TC monotherapy TI (MTI), were collected. Descriptive statistics and univariate testing were used to compare children with TI and MTI to children on continuous treatment (CT).3 vs. 815 cells/mm3; p=0.003) and CD4%  were observed in the TI cohort as compared to the CT cohort. The median endpoint VL in the overall TI cohort was ~4 times higher than among the CT cohort . After a median TI duration of one year, a majority  of patients with TI restarted cART, including 100% of those with total TI and 53% of those on MTI, respectively.Thirty-eight (28%) out of 136 enrolled children (median age=12.9 years) experienced TI, with 14 (37%) of those placed on 3TC MTI. Significantly lower endpoint median CD4 counts (598 cells/mmIn our study, we observed high frequency of the TI in HIV in paediatric HIV clinical practice. All TIs, including 3TC MTI, were associated with significantly lower endpoint median CD4 counts and higher median VLs, as compared to CT in paediatric patients. The high frequency of TI and associated poor outcomes suggest a need for a better strategy in managing the course of the paediatric and adolescent cART. Combination antiretroviral therapy (cART) has dramatically improved the outcome of paediatric HIV infection. Supported by the evidence from the START trial, the 2015 World Health Organization HIV treatment guidelines recommend a universal start of cART in all HIV-infected individuals including children and adolescents ,4.With changes in the child's age and maturity, paediatric cART evolves from the administering liquid and powdered/granulated antiretroviral drugs (ARVs) to swallowing fixed-dose combinations tablets. This transition requires frequent adjustment of ARV dosing based on the child's age and weight and close monitoring for cART tolerability and toxicity. Adherence barriers also continue to evolve from acceptability of paediatric ARVs in infancy to increased peer pressure and disclosure challenges during puberty –7. MoreoTogether, these challenges create multiple settings for treatment interruptions (TI) of cART from infancy into adolescence. Paediatric and adolescent HIV providers have considered structured TI guided by CD4 count and clinical staging of the disease –13. TI aWhile existing data support the feasibility of structured TI in children, data on the long-term effects of TI in paediatric HIV-infected patients are limited ,12. In tThis analysis was conducted as part of a larger city-wide longitudinal cohort study of HIV-infected persons receiving care in the District of Columbia (DC), which is aimed to describe clinical outcomes and improve the quality of care for patients in Washington, DC, USA . The paeHIV-infected children and adolescents (aged 0–24 years) treated at SIS were eligible to participate. Informed consent (parents and participants ≥18 years of age) and assent (7–17 years of age) were required. The study protocol was approved by the Institutional Review Boards (IRBs) at the George Washington University (GWU) and CNHS.Demographic data  and retrospective immunologic , virologic ) and antiretroviral therapy (age at initiations of ARVs and ARVs prescribed) data were collected from the medical records (MR) of patients enrolled into DC cohort during 2011 to 2013. Immunologic and virologic data collected at the time of enrolment through 2013 were used as endpoints across the overall study cohort.four consecutive weeks of discontinuation of cART, including placement on monotherapy TI (MTI), approved/prescribed by a clinical provider and documented in the MR. Within the TI cohort, the patients who underwent a TI with no ARVs prescribed were classified as having total TI (TTI). Patients who interrupted cART but were instead prescribed a single ARV 3TC or LPV/r were classified as MTI cohort. A patient with multiple TIs was analyzed as one unit using the data associated with the longest TI period. Patients on cART who did not have TI were classified as the CT cohort. TI data included age at the start and end of TI, reasons for TI, CD4 count and VL closest to the time of starting TI and after the restart of cART, maximal CD4 count prior and after TI and time to reaching maximal CD4 count after restarting cART.TI was defined as a period of at least Frequency distributions and summary statistics, including median and interquartile range (IQR), were used to describe the demographic, clinical and treatment characteristics in general and between those on CT compared to those with TI. Comparisons between groups (CT vs. TI and TTI vs. MTI) were performed using chi-squared and Wilcoxon rank sum tests as appropriate. Among those in the TTI cohort who restarted treatment, maximum CD4 count and VL before and after TI were compared using Wilcoxon sign rank test. Data were analyzed using SAS 9.3 .3 and 31%, respectively. Approximately half of the study cohort had undetectable or very low VLs with 60 (44%) and 15 (9.4%) patients with HIV RNA VL <48 copies/mL and >48 to <200 copies/mL, respectively (data not shown). Among those with detectable VL, the median HIV RNA VL at enrolment was 3397 copies/mL.From October 2011 through December 2013, 136 patients were enrolled . The majThirty-eight (28%) participants experienced at least one TI since initiating ARVs. There were six patients with more than one episode of TI lasting at least four weeks. There were no statistically significant differences in demographic characteristics between the TI and CT cohorts .p=0.003, 0.006 and 0.04, respectively; p<0.0001).The median CD4 count, CD4% and nadir CD4 count were significantly lower in those who experienced TI as compared to patients in the CT cohort  had experienced TTI of cART. Among the remaining 15 (36.8%) children with TI, 14 (93%) patients with known resistance to 3TC were placed on 3TC MTI, and one patient was switched to LPV/ritonavir MTI (data not shown). In the overall TI cohort, the median CD4 count prior to TI was 789 cells/mm3 and the median VL was 2362 copies/mL. The most common reason for TI was non-adherence (29%), followed by viral resistance with limited options for alternative cART (11%) and ARV-related toxicity (5%)  . In 29% ity (5%) .n=23; 100%), while only 8 out of 15 patients (53%) on MTI restarted cART. The highest CD4 count ever reached prior to TI (1509 cells/mm3 (IQR 1137–1820)) was significantly higher than the maximal CD4 count ever reached after TI (706 cells/mm3 (IQR 531–1140); p=0.0005), most likely due to the increased age. TTI and MTI groups did not demonstrate any significant differences in demographic, immunologic or virologic characteristics (data not shown). The only finding in this sub-analysis was the shorter time required by patients in the MTI cohort (two months (IQR 1.4–3.5)) to reach their highest CD4 count after restarting cART as compared to the patients in the TTI cohort (7.9 months (IQR 4.2–22).All patients with TTI restarted cART  was similar to that reported across the observational studies of unstructured TI from developed countries reporting TI in up to 40% of paediatric populations –28. Many% was simp=0.001) decrease in CD4% among children and the history of any TI was associated with a trend to increased mortality (hazard ratio: 2.6 (95% CI 0.7–10.4)) [Several studies have suggested higher immunologic resilience and rebound following prolonged TI in children due to the inherent differences in immune system maturation compared to adults ,12,21,23holding or bridging regimen using 3TC or emtricitabine (FTC) monotherapy in the presence of the M184V HIV resistance mutation to reduce viral fitness and prevent formation of additional resistance mutations [n=17) randomized to 3TC MTI were more likely than those maintained on failing cART (n=16) to sustain a ≥30% decline in CD4 count [Structured TI has been linked to utations ,15. IMPAutations . ParticiD4 count . Recent Due to the developmental changes throughout childhood and adolescence, TI represents an ongoing challenge to the continuum of paediatric cART. Prolonged TI can have potentially detrimental effects on the long-term outcomes in HIV-infected children. In our study, significantly lower median CD4 count and higher median VL were observed in children with a history of TI, including patients on 3TC MTI, as compared to those on continued cART. A sub-group analysis suggests a trend for a shorter time for 3TC MTI cohort to reach their highest CD4 count after restarting cART, which warrants further evaluation. Finally, the high frequency of TIs reported in our and other paediatric studies suggests a need for a better strategy in maintaining the continuity of the paediatric and adolescent cART.


In the quest to achieve early HIV treatment goals, national HIV treatment programmes dependent on international funding have been dramatically redesigned over the last 5 years. Bottlenecks in treatment provision are conceived of as health system problems to be addressed via structural and logistical fixes . Patient perspectives are rarely taken into account when such fixes are being considered. Patients’ therapeutic experiences often remain at the periphery during the planning stage and are only considered within the context of monitoring and evaluation audits once programmes are up and running.Ethnographic research was conducted in five clinics in Swaziland between 2012 and 2014. Participatory approaches were used to collect data; the first author trained as an HIV counsellor in order to collect observational data on the continuum of care, and conducted in-depth interviews with interlocutors involved at the different phases.Although recently adopted global HIV strategies have proven effective in scaling up treatment in Swaziland, our research demonstrates that the effort to expand services rapidly and to meet donor targets has also undermined patients’ therapeutic experiences and overtaxed health workers, both of which are counterproductive to the ultimate goal of treatment scale-up. This article provides a perspective beyond the structural elements that impede universal treatment, and explores patient views and experiences of the strategies adopted to support further treatment expansion, with a particular focus on the shifting of key care and logistical tasks to expert clients.We argue that in the quest to achieve universal early access to treatment, both donors and states must go beyond strengthening health systems and strive to enhance the quality of patient experiences and take seriously health worker limitations. Research for this article was collected within the framework of a larger research and intervention project in Swaziland known as MaxART .Beyond the structural factors limiting the expansion of ART that the MaxART project aimed to eliminate, our research identified several other important factors that limited individual uptake of services. Even when health facilities were easily reachable in terms of distance, and fully staffed and equipped, some people still did not utilise the services as expected. This article describes such other factors that impede treatment, and explores patient experiences of and perspectives on the processes and strategies adopted to support the further expansion of treatment, with a particular focus on the shifting of key care and logistical tasks to expert clients.Most monitoring and evaluation frameworks track results: number of people tested, enrolled, and retained in treatment programs. By focusing on everyday practices of care within the context of ART clinics we provide important information about the ways that gaps in the HIV care continuum are created in situ. Our approach, combining ethnographic observation and qualitative interviewing, allowed us to examine both the social and logistical processes involved in achieving these numbers, and to draw attention to the intensive labour of the non-medically trained workers who assist patients to navigate these processes. This article builds on a growing body of qualitative research on task shifting.In 2006, during the High-Level Meeting on HIV/AIDS for the United Nations General Assembly, the UN committed to work towards universal access to ART by 2010. At the time, there were glaring health system weaknesses in many of the countries hardest hit by HIV, particularly with regard to human resources. The ‘treat, train, and retain’ plan was devised by WHO  as a resAt the time, task shifting in the context of HIV-related health services was already being practiced in Swaziland. Lay health workers, predominantly PLHIV, were taking over some nursing tasks, including HIV counselling, whilst nurses took over some of doctors’ duties to start patients on ART. Beyond the context of HIV, nurses had long performed tasks that were officially reserved for medical doctors, for example administering intravenous medicines and doing sutures.In 2006 the Swazi Ministry of Health decentralised ART provision to the lowest levels of the health system, which resulted in the need to expand the health workforce. The health system was already facing a formidable human resource crisis due to a combination of factors including ‘brain drain’, with Swazi medical professionals often migrating, and a low health worker output in the country. The total number of nurses graduating annually in Swaziland was only 80, far below the numbers required for treatment expansion. Two years after ART became available for free in public health facilities in Swaziland, Kober and Van Damme  examinedIn order to meet these demands, a new cadre of lay health workers, expert clients, was introduced in health facilities. A year after the use of expert clients in task shifting was officially instituted in the country’s ART programmes, Samb and colleagues  reportedIn Swaziland, an expert client is someone who is living with HIV and actively taking antiretroviral medications, who has demonstrated good adherence to treatment, encourages others living with HIV to seek treatment, and is willing to disclose his or her status and share the experience of living with HIV with other patients. Seen as model patients, expert clients live a ‘normal life’ despite HIV infection. They are hired as full-time, minimally paid volunteers to work within health facilities as health workers. In the clinics where we conducted research, expert clients had initially been engaged to provide counselling. However, over the years as the need for more health workers grew in the context of treatment expansion, the tasks of expert clients expanded to include: HIV testing, pre- and post-test counselling, enrolment of patients into care, booking patients for appointments, adherence counselling for patients on ART, and patient tracking. There are two ways to become an expert client in Swaziland: one can respond to an advertisement, which is normally placed on a clinic’s bulletin board and lists the above mentioned attributes, or an ART nurse can identify an adherent patient as a good candidate. Additionally, each candidate undergoes an interview and an offer is made to the best candidate. Before expert clients start working in health facilities, they are trained for 6.5 days following a curriculum which consists of 14-units: introduction to HIV, HIV basics, paediatrics and HIV, impact of HIV, role of expert clients, communication and counselling skills, HIV care and treatment, adherence to treatment, stigma and disclosure, positive living, record keeping, referrals, facility-community linkages and a practicum.This article draws on 25 months of ethnographic research (June 2012–July 2014) conducted in Swaziland to examine the HIV continuum of care in public health facilities. The aim was to identify the social and logistical dynamics that contributed to delayed uptake of ART and for patients dropping out of HIV-related care. To better understand the delays and disruptions occurring in the care continuum, we focused our investigation on the health system itself, paying attention to logistical and human resource issues. As part of the main study, we hypothesized that care and treatment access were shaped by factors beyond the clinic, however, we also examined wider sociocultural norms that shaped access to care and treatment-for example norms relating to gender, marital status, and age-as well as the perspectives of individual patients [fundza sites) as an intern in an HIV counselling course (HTC); two additional clinics (gusta sites) were also selected for in-depth ethnographic research. Two of the fundza research sites were located in the city centre of the, and one was located in a peri-urban area. The two sites located in the city were highly-resourced hospitals that were fully equipped and served as ART initiation sites. Because they received private funding, they were not entirely depended on donor funding or government. The gusta sites were not in urban setting; one was located at the periphery of the capital city and the other in a rural area approximately 200 km from the capital city. They were both community clinics and primarily dependant on government funding and donor supported. Findings presented in this paper were derived from participant observations and time series in-depth-interviews (IDIs) with patients who were eligible but did not initiate ART in 2011. At the onset of fieldwork, the first author enrolled in a 5-week HTC course and trained as an HIV counsellor. Two weeks of classroom training on the theoretical aspects of HIV counselling were followed by 3 weeks of practicum providing HTC services to patients testing for HIV. At completion of the training the first author became a certified HIV counsellor, which permitted her to be part of the counselling team in three clinics where she collected observational data.Data was collected from five clinics. The first author was attached to three clinics , the first author observed 136 HIV counselling sessions over a period of 20 months. During these observations, she took detailed notes to record the type of information provided to patients following HIV diagnosis, the manner in which it was delivered, the behaviour of patients in the counselling room, and how counsellors interacted with returning patients who had missed clinic appointments. Additionally, the first author assisted counsellors as they executed their daily duties, helping to track patients, sorting patient files, filling registers, and booking patients for future appointments. Research in these two clinics allowed the first author to compare working as a counsellor with the practices of health workers in routine clinical settings.At the two additional clinics (gusta) clinics where in-depth research was conducted. The first author was on-site full time at each clinic for 2 months, observing clinical operations in all departments, including the laboratory, the ART nurses’ station, consultation rooms, and the dispensary where she assisted in the packing of medicines. After the 2 months, she continued to return periodically to each clinic to follow up with particular patients and health workers until the end of the research period.Observations went beyond the counselling room to include the entire ART department in each of the two  among lay workers, nurses, other clinic staff, and patients.In-depth semi-structured interviews were conducted with participants purposively selected from two sources: patients observed in the counselling room and patients identified as ‘defaulters’ by counsellors. HIV-positive persons eligible to begin ART were scheduled for a series of counselling appointments. If a client failed to show up for an appointment, the counselling staff put the client’s file into a stack of defaulters. From those files, we narrowed the pile to include only those who had been scheduled to start ART in 2011 to tally with the beginning of the MaxART project. Counsellors routinely telephoned defaulters to ask the reason for the missed appointment and then reschedule. When patients reported back to the clinic, they were approached and invited to participate in the study after being informed of the study parameters and giving consent by signing a consent form.Selection criteria limited participants to patients who had failed to return to the clinic for scheduled appointments, and patients who verbally stated not wanting to take ART medications as their reason for defaulting. Of the 93 patients who met the selection criteria, 71 agreed to be interviewed and a total of 104 interviews were conducted. Of the 22patients who were not interviewed, several refused and others proved impossible to track.Interviews were conducted at a place and time convenient to the participants, and were conducted in siSwati, the first language of both the first author and the participants. Interviews began with informal conversations. Patients were then invited to speak about their overall experiences at the clinic in general and specifically why they had not returned for previously scheduled appointments. Data collection was an iterative process that allowed for crosschecking findings with subsequent research subjects to come up with themes until saturation was reached. Interviews lasted between 30 and 120 min, they were transcribed in siSwati, and then translated into English by the first author.All observational data from the counselling course was recorded as field notes, especially system-related dynamics and processes that would potentially cause patients to drop out of care. The data was analysed daily and, following the second week of the practicum, was categorised into themes. Recurring process flaws observed in the second week were matched with corresponding themes already identified. In the two ethnographic research sites, the analysis framework developed was matched and contrasted with recurring themes until the research process ended. Themes that emerged from the observational data were explored further via in-depth interviews with patients and health workers to seek the perspectives of both. NVivo was used for content analysis when data collection was completed to identify recurring and overarching themes. The themes were also analysed per research site to identify convergences and divergences in data.The formal introduction of task shifting in HIV clinics in Swaziland introduced a new cadre of health workers and multiple new processes and strategies as clinic functions grew and the various tasks of doctors and nurses expanded and shifted. Observations allowed us to track the variety and extent of the changes in clinic policy and practice that accompanied the formal introduction of task shifting. This section highlights the ways that task shifting affected health care delivery and practices in the clinics where it was implemented and, further, how it affected patient experiences. Task shifting in the study sites entailed nurses initiating ART, a service previously rendered by doctors, and nurses delegating tasks to expert clients. The tasks shifted by nurses to expert clients included HIV testing, pre- and post-test counselling, enrolment of patients into care, adherence counselling for patients on ART, and patient tracking. Previously, expert clients working in clinics as PLHIV volunteers had provided psychosocial support to newly diagnosed HIV-positive people; with task shifting, they had to double as HIV counsellors and nursing assistants.Can you imagine, you have a headache and you feel the pain now, but instead of being given medication now you are told to do 1, 2, and 3 first. They told me I am HIV positive, the cause for my running stomach, so I need to take treatment. I said I was ready to take treatment home that very day but they said that it doesn’t work like that .Contrary to expectations, our data suggests that task shifting has not resulted in improved quality or more patient-friendly services. Patients must now pass through ‘too many hands and processes’ before they finally get the services they seek. I met Sibakhe, a 27-year-old man, 2 weeks after he was tested and diagnosed with HIV, who was frustrated that he still was not on ART. He had wanted to start ART immediately after diagnosis, but was told he needed to first go through a lengthy process to prepare him for ART. Expressing his dissatisfaction with the process, he told me:When I discovered I was HIV positive it was a difficult time in my life. It took me 5 months to finally agree to start treatment. I became aware of people I know who are on ART. That is when I counselled myself and I went straight to the clinic. The process was explained to me, that I had to do various tests and three counselling sessions before I could start treatment. I finished the counselling, and the results from the national lab were pending. I became distraught when 1 month passed and there was no word from the clinic about my results. I went back to the clinic three different times to check my results and they were still not back. It has been more than 2 months waiting for them and I am worried whether I will ever initiate ART and get my health back like others taking ART. Similarly, Tukisa had learned of her HIV status 6 months before we met. She had been waiting for 2 months for the clinic to call her with her chemistry results from the national laboratory. This resulted in a bottleneck in her treatment trajectory as the test results were a prerequisite for ART initiation.These interview excerpts show the frustration that patients often reported. From the patients’ perspective, they were ready to start treatment so they could begin healing, but the mandated process for patients newly diagnosed with HIV involved numerous steps that are spread out over several clinic visits. From the patient’s perspective, postponing treatment to a future date does not make sense, especially when they are not feeling well and are ready to start taking medicines. The delays in HIV treatment initiation are tied to procedure that stipulate three counselling sessions prior to starting treatment, as well as delays in getting laboratory results. Such bottlenecks are unique to HIV treatment in Swaziland, and have been exacerbated by the country’s test and treat initiatives. The solutions-introducing a new cadre of workers and mandating a multi-step treatment initiation process, with different health care workers responsible for each step-have led to a situation where patients have to pass through too many hands to access treatment. Although these solutions were put in place to resolve the high volume of patients, unfortunately they also frustrate patients, resulting in delayed treatment uptake for those ready to start treatment as soon as possible. In some cases, frustrations with the health system, combined with the social and economic challenges of multiple clinic visits, lead to patients dropping out of care altogether or choosing to delay treatment until they are very sick.Treatment delays resulting from clinical procedures were confirmed by our own observational data as illustrated in Fig. Before the move toward a global test-and-treat framework and the introduction of task shifting in Swaziland, individuals wanting to test for HIV would visit a voluntary counselling and testing (VCT) site, where they would receive pre- and post-test counselling, tested for HIV, and received test results, all from one health worker. As we have detailed elsewhere, , with taThe conversations I had with health workers who worked in HIV care delivery prior to the introduction of task shifting, indicate that the norm was for one health worker to administer the initiation of a patient into care at clinics in Swaziland. A patient usually only queued once per clinic visit, at most twice if including the collecting of medicines from the dispensary. According to nurses, the maximum time spent at a clinic should not exceed three hours. Yet, a patient testing for HIV must queue at up to seven service points in one day to complete the requisite steps associated with diagnosis. Our observations at the clinic recorded patients spending a minimum of three hours per clinic visit, with some patients spent up to six hours to complete the required steps. Thus task shifting not only multiplied the number of health workers a patient must see during a visit, but also extended waiting times. In addition, the current set-up also introduced greater possibilities for confidentiality breaches, as well as psychological burdens on patients who have to interact with multiple health workers on what is already a very stressful day for most.Once the diagnosing processes are completed, those who test positive must embark on a second protracted journey to prepare for treatment initiation.Figure The procedures and processes that accompanied treatment scale up and task shifting were introduced to streamline access to treatment and reorganise the health system to accommodate a rapidly growing number of patients. The steps illustrated in Fig. gusta clinic. However, if the PIMA broke down, patients would have to return to the clinic at a later date to do the CD4 count. This sometimes meant more than one trip depending on how quickly the PIMA was fixed or a new PIMA installed. During the second clinic visit, patients had to give three tubes of blood to be sent to the national laboratory for blood chemistry analysis, a service that was not available at the primary health facilities. Each clinic was given specific days of the week for drawing blood and the collection of blood specimens for chemistry profiles to ensure the specimens reached the lab in good condition. If a client was diagnosed and became eligible for ART on a day that did not fall within the blood collection days, it meant the client had to return to the clinic on another day.The seven mandatory clinic visits illustrated in Fig. Beginning with the third clinic visit, patients begin a three-step counselling process meant to prepare them to make a lifelong commitment to ART adherence. The treatment guidelines stipulate that a client must attend three successive ART counselling sessions, with a minimum of seven days in-between sessions to assimilate and process information. If patients were able to return every week as planned, the pre-ART counselling phase would last 3 weeks at minimum. The three sessions were mandatory, regardless of the patient’s desire to start treatment sooner or a counsellor’s assessment of patient readiness.An additional clinic visit was required to collect blood chemistry results. Patients were given a 2-week turnaround time before returning to the clinic to check their results from the national laboratory. However, some patients waited much longer than 2 weeks because samples sometimes spoilt during transportation from clinic to laboratory, which meant that a fresh specimen had to be taken and meant another 2 weeks in wait. Other delays were caused when; samples were lost or mixed up, when laboratory equipment at the national laboratory broke down, and when reagents were out of stock. During the research period, the country experienced a 4-month stock-out of reagents, and such was not uncommon. During that period it meant countrywide, no new patients could be started on treatment. Additionally, all patients who had given blood in the lead up to the stock-out had to return to the clinic to have fresh blood drawn . Obviously, such breakdowns and delays are bound to cause lack of trust in the system, as well as feelings of frustration and betrayal.gusta clinics were given targets to reach every month: number of people tested, enrolled into care, successfully tracked and linked to care, and adherence rates. In the gusta clinics, a report showing a decline in these statistics would be a nightmare for counsellors, which is expert clients. Because HIV counsellors stipend was paid by implementing partnersTreatment expansion has been characterised by a push to meet set targets that put a lot of pressure on health workers . The gusThe pressure to attend to high patient loads meant that health care workers could spend even less time with patients than their already busy schedules allowed. From our observational data, we were able to calculate that on average nurses in both clinics saw up to 70 patients in a busy day during the first and last week of the month. The number was higher for expert clients because they also attended to patients who did not have to see the nurse, such as those receiving pre-test counselling (SP2) and those counselled in preparation for ART (SP6). In view of such realities, ethical issues and conduct, as well as quality of care were sometimes compromised in practice. Under immense time constraints and pressure to perform, expert clients sometimes passed their frustration onto patients. They were often authoritative and disciplining during counselling sessions.gusta sites, two counsellors shared one room and gave only standardised messages during counselling. Little if any attempt was made to create the context for an open and honest dialogue. Furthermore, it seemed that counselling messages were primarily intended to get patients to adhere to treatment at all costs rather than to support them as they attempted to deal with the complex social and cultural dynamics of an HIV infection or things that could potentially impede uptake of treatment . For example, one counselling session for a non-adherent patient seemed more like a court session, where the patient was treated as if he had broken a law and was punished through humiliating verbal reprimands. Utterances commonly used during counselling sessions included ‘we will send police to get you if you refuse to take treatment’ and ‘you will get a resistant strain of the virus if you don’t take medication properly, and die’. Such findings confirm similar trends identified by others researching counselling in the age of treatment scale-up [During HTC training, counsellors were told that a good counselling session requires ‘a counsellor to have big eyes, big ears, and a small mouth’, meaning a good counsellor must be observant, pay attention to the patient in order to notice even bodily cues, and must listen more and talk less. However, the opposite was often observed in practice; counsellors dominated conversations and dictated to patients. Another principle stressed during the counselling training was that of confidentiality. Confidentiality depends on the counsellor having enough time in a private space to discuss the patient’s history and health status. In practice, patients were counselled in open and shared spaces; in one of the scale-up , 15 counBack in the days when ART started, we did not take tea and lunch breaks as long as there was a patient waiting, we had to rotate, this is no longer the case. How much can one put in when you don’t get anything back? We work so hard and even on weekends as many things are added in our jobs because of HIV, but there is no incentive. They don’t even care that we need psychological support and debriefing as health workers. We used to have annual workshops in hotels, which gave us an opportunity to interact with our peers about our work in a more relaxed environment and a form of consolation. It was therapeutic for us. We observed that the pressure associated with treatment expansion-reaching targets, limited resources-coupled with burnout, gradually reduced the competence of nurses as they became less enthusiastic and less vigilant in their work. In an interview with an ART nurses, she said:They tell us how to do things and sometimes we are confused because we get different instructions. ICAP says this, World Vision says that, and the Ministry of Health the other thing. So we wait until they discuss and get direction from them because with HIV our discretion is limited. There is a lot we do not know, there are many changes, and we have to rely on guidance. Increased workload has been associated with reduced performance and less sensitivity towards patient needs of –18. MabeMuch of the work performed by nurses within the ART programme was learnt on the job rather than in formal training. The avalanche of protocols and dependence on mentors for technical support in provision of care limited nurses’ ability to apply discretion in providing care and resulted in limited competence. In some cases, however, the nurses simply lacked sufficient training. The first author witnessed patients given the wrong treatment or turned away because the nurse was unsure how to intervene. Also in one case, a patient presented with a condition that was a side effect of one of the ARV drugs she was taking. Although the expert client knew about the problem, the nurse did not.Generally expert clients had greater competence than nurses when it came to taking HIV medicines. They knew the different types of pills by name and sight and quickly noticed if a client had received the wrong medication. Due to the increase in such errors, expert clients in the clinic made it their prerogative to check the patients’ medicines before they left the clinic. Such practices shaped the patients’ experience dramatically. Expert clients were increasingly positioned to serve patients better than nurses, taking up some of the technical tasks that were left for clinical acumen. The danger of patients being given the wrong pills due to the under-training and over-working of nurses cannot be over-emphasised. Beyond that, nurses experienced a decrease in power at the expense of expert clients, which sometimes translated to tensions in the workplace, see also , 21.policypeutic to capture how policies have intrinsic meaning and are relationally experienced and embodied by the intended users.As conceptualised, task shifting was intended to resolve human resource challenges needed to expand treatment, to ensure the sustainability of programmes, and to improve quality of care of patients through the simplification of processes and the provision of patient-friendly services . Our finFurthermore, the derived policies do not always come with all the support required for the strategies to work efficiently. Efforts to rapidly expand treatment were made by bringing comprehensive services to the grassroots level , however there were many logistical challenges encountered by the clinics: spoilage of blood samples, breakdown of equipment, delays in tests results. Due priority was not given in resolving these interruptions which were key to the treatment scale-up plan. This became visible during the four-month stockout of reagents that occurred during the course of the study, yet more patients were enrolled whilst many were lost as their results did not return from the national referral laboratory.In ideal circumstances, a compliant patient in Swaziland waits an average of 2 months before treatment begins due to mandatory procedures. Long waits and bureaucracy can be a disincentive for eligible patients . The newHowever, measured against project-determined ‘audit rituals’ , 24, theTask shifting has unquestionably alleviated the acute human resource situation and facilitated the massive expansion of HIV treatment programmes in Swaziland and across Africa. But it was never going to be a permanent fix for the continent’s human resource issues. Africa produces a meagre 5,100 medical doctors per annum . AddressTask shifting becomes a stopgap solution that leads neither to sustainability or the strengthening of health systems, nor to the accelerated training of health workers required to meet the national demands of the ART programme. Therefore strengthening of the health system should be a priority and task shifting is one such a strategy that needs to be implemented, to compliment treatment expansion efforts. That said, promotion of new strategies need to foster positive therapeutic experiences and better outcomes for patients than just purely focusing on arithmetic targets. The authors recommend that evaluation of HIV programmes and interventions should incorporate metrics that can account for the quality of services and also take into account the views and experiences of on-the-ground, healthcare workers and patients. The case of Swaziland serves as an important example for other countries attempting to scale-up HIV treatment rapidly. Although other countries in Africa and elsewhere have been expanding access to treatment over the last decade, the Swazi ‘experiment,’ offers insights into the dangers of emphasizing reaching short-term targets that might affect issues of quality service delivery and long-term sustainability. Given the immense funding and technical expertise funnelled into Swaziland in a very short period of time, the recent national effort to scale-up treatment is somewhat unique, especially given that HIV testing and treatment rates were so low in Swaziland prior to the recent push. Given the focus of this article, we refrain from examining the Swazi “success” in comparison to other countries. Instead, we have tried to highlight some of the ‘failures’ concealed by the Swazi success story.Although Swaziland has managed to get many more people in need to test for HIV and to enrol in treatment programmes in a very short period of time, it remains to be seen if the health system can sustain the level of success it has demonstrated, if people can be kept on treatment over the course of their lives, or if overburdened healthcare workers can be supported in their careers, both materially and psychologically. HIV treatment is for life, the life of those infected, as well as the life of those providing care. Swaziland may be winning in the sprint competition, but the marathon lies ahead.The Swazi experiment also offers insights into the dangers of the bureaucratization of HIV care delivery. The Kafkaesque proliferation of service points in Swaziland has actually increased the length of time people have to wait for services on any given day and also the time between finding out one’s HIV status and being enrolled in a treatment programme. This has created frustrations, economic expense, and psychological distress for patients. Although we support the aim of collecting evaluation data to improve services, we question the motivations of donors who insist on making treatment programmes more complex to allow them to meet the demands of internal organizational monitoring and evaluation frameworks. Finally, given the very important role that expert clients play in filling the multiple gaps in HIV care provision, we argue that national health ministries should move to regularize this cadre of health workers to ensure continued employment for them and the sustainability of treatment programmes as a whole.


Aim of this review is to focus the attention on people living with HIV infection at risk of developing a cardiovascular event. What is or what would be the most suitable antiretroviral therapy? Which statin or fibrate to reduce the risk? How to influence behavior and lifestyles?Prevention of cardiovascular disease (CVD) risk remains the first and essential step in a medical intervention on these patients. The lifestyle modification, including smoking cessation, increased physical activity, weight reduction, and the education on healthy dietary practices are the main instruments.Statins are the cornerstone for the treatment of hypercholesterolemia. They have been shown to slow the progression or promote regression of coronary plaque, and could also exert an anti-inflammatory and immunomodulatory effect. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. The debate between American and European guidelines is still open and, also considering the independent risk factor represented by HIV, specific guidelines are warranted.Ezetimibe reduces the intestinal absorption of cholesterol. It is effective alone or in combination with rosuvastatin. It does not modify plasmatic concentrations of antiretrovirals. A number of experimental new classes of drugs for the treatment of hypercholesterolemia are being studied.Fibrates represent the first choice for treatment of hypertriglyceridemia, however, the renal toxicity of fibrates and statins should be considered.Omega 3 fatty acids have a good safety profile, but their efficacy is limited. Another concern is the high dose needed. Other drugs are acipimox and tesamorelin.Current antiretroviral therapies are less toxic and more effective than regimens used in the early years. Lipodistrophy and dyslipidemia are the main causes of long-term toxicities. Not all antiretrovirals have similar toxicities. Protease Inhibitors may cause dyslipidemia and lipodystrophy, while integrase inhibitors have a minimal impact on lipids profile, and no evidence of lipodystrophy. There is still much to be written with the introduction of new drugs in clinical practice.Cardiovascular risk among HIV infected patients, interventions on behavior and lifestyles, use of drugs to reduce the risk, and switch in antiretroviral therapy, remain nowadays major issues in the management of HIV-infected patients. In the recent years we observed an improvement of survival and quality of life in people living with HIV (PLWHIV), due to the success of combined antiretroviral treatment (cART) .The early treatment, the reduced toxicity of antiretroviral regimens and the fading of thymidine-analogues-based regimens and the high dosage of ritonavir represent less atherogenic antiretroviral agents for most PLWHIV. This is not enough since PLWHIV live longer, thus in addition to age they add up all degenerative diseases caused by HIV and the side effects of antiretroviral drugs.This should encourage physicians and researchers in seeking the patient’s well-being, not only through HIV-RNA suppression, but thinking about other more ambitious goals, perhaps more distant from infectious diseases.Aim of this review is to focus the attention on PLWHIV at risk of developing a cardiovascular event. What is the most suitable cART? Which statin or fibrate to use in order to reduce the risk? How to influence behavior and lifestyles? Everything in the coming years will be played in this field, so we must be prepared.lifestyle” is generally based on established patterns of behaviour over time, which have been internalized from childhood and adolescence through the interaction of genetic and environmental factors and that are maintained or even encouraged by the social context in adulthood age.An inappropriate lifestyle, in particular smoking, reduced exercise, unhealthy diet and psychosocial stress are responsible for an increased CVD risk. The “2.The dietary habits and physical activity in particular are key factors for the reduction of CV diseases: risk factors such as alcohol use, high blood pressure, high body mass index, hypercholesterolemia, diabetes, low fruit and vegetable intake and physical inactivity, collectively account, with smoking, for more than 60% of cardiovascular deaths globally . Energy The wide variety of foods of animal and vegetable origin is the basis for a healthy and balanced diet. Many published data show that the Mediterranean diet appears to be protective against cardiovascular disease and total mortality. The use of this type of diet can have beneficial effects not only on prevention of the main CVD risk factors but also on the course of the disease once it presented. The recommendations of the Mediterranean diet are reasumed in Table Smoking remains the main responsible for the majority of CVD . The 10-Preventing PLWHIV from starting smoking is critical, because stop smoking remains a formidable challenge. Although the percentage of smokers is declining in Europe, it still remains high and is rising in women, including adolescents and people socially disadvantaged . WideninSome studies have investigated how much the increased mortality in PLWHIV was attributable to smoking. In 2013, a Danish study  observedFinally, it as to be remembered that some ways in which people cope with stress such as drinking, smoking or overeating, are not healthy especially in PLWHIV.Switching from current cART to a more lipid-friendly regimen may represent an option to improve dyslipidemia and to reduce cardiovascular risk in PLWHIV. The principles of cART switching also in the setting of dyslipidemia are to maintain virologic suppression, improve adherence and tolerability , 11. RegAt the CROI 2017, much attention was centered on the D.A.D, findings on darunavir (DRV) in regards to the development of cardiovascular events. Their analysis had been based on 7 years of follow-up and linked the cumulative use of DRV/r to a gradually increasing risk of CVD . CVD incIn the class of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), dyslipidemia has been associated with exposure to stavudine, zidovudine and abacavir, whereas tenofovir disoproxil fumarate (TDF) has been noted to have a favourable lipid influence , 16. In Switching within NRTIs: there is evidence of improvement of total cholesterol (TC), LDL-C and TGL switching from abacavir (ABC)/lamivudine to TDF/emtricitabine (FTC) , 24.Switching from protease inhibitor boosted (PI/r) to NNRTIs: Most data on effect of switching from PI/r to nevirapine or efavirenz derived from the early cART era , 26. In Switching from PI unboosted to NNRTI: in a most recent observational trials switch from unboosted PI to RPV has been associated with significant improved of lipids parameters .Switching from PI/r to an INSTI: Switching studies from PI/r to raltegravir (RAL) (SWITCHMRK and SPIRAL) demonstrated a significant lipid and cardiovascular biomarkers reduction in RAL arm. However, in the SWITCHMRK study it was noticed an increased risk of virologic failure that was probably linked to a bias in the patient’s selection , 31. In Antiretroviral therapy suppresses viral replication and reduces the concentration of systemic immune activation markers , 34 and During the first 3 months after the switch, the patient should be closely monitored to assess tolerability and adherence to new cART regimen.HIV-RNA test may be performed to check for rebound viremia 4 weeks after the switch and then every 3 months during the first year; fasting lipids (cholesterol and triglycerides) should be assessed within 3 months after the change and every 3 months during the first year. In absence of new complaints, subsequent monitoring should be performed on a regularly scheduled basis , 11.Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir disiproxil fumarate (TDF). In this new formulations TAF show higher levels of TDF-DP in periphereal blood mononuclear cells and lymphoid tissues than TDF. TAF showed safety advantages compared to TDF containing regimen regarding bone and renal toxicity , regardiCabotegravir is an investigational HIV INI drug, currently being studied in Phase IIb clinical trials. During preliminary studies conducted on healthy subjects both in monotherapy and in combination with RPV , 40 no cDoravirine is a NNRTI currently being studied in Phase III clinical trials as both a single-drug tablet and as part of a fixed-dose combination tablet. In a preliminary study with single and multiple doses of doravirine in healthy subjects, no serious adverse events were reported, and there were no consistent, clinically relevant, treatment-related effects of doravirine on vital signs or ECGs. Overall, no clinically significant trends or signals were observed in laboratory assessments, vital signs or ECGs . In a raStatins are the cornerstone of the treatment of hypercholesterolemia. They reduce the synthesis of cholesterol in the liver by competitively inhibiting the hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. The reduction in intracellular cholesterol concentrations induces LDL receptor expression on the hepatocyte cell surface, which results in increased extraction of LDL-cholesterol (LDL-C) from the blood and a decreased concentration of circulating LDL-C and other lipoproteins including triglycerides-rich particles.A number of large-scale clinical trials have demonstrated that statins substantially reduce cardiovascular (CV) morbidity and mortality in both primary and secondary prevention , 48. In Meta-analyses of randomized controlled trials that focused on primary prevention, demonstrated that in people without established CV disease but with CV risk factors, the use of statins was associated with significantly improved survival and large reductions in the risk of major CV events , 49. BenThe most recent clinical trials suggested that the LDL-C lowering effect of statins between PLWHIV is similar to that seen in the general population. Several randomized studies of hypercholesterolemic HIV-infected patients showed that LDL-C decreased by 15% to 35% in patients taking statins as compared with placebo . In a trRecently, statins have also been shown to slow the progression or even promote regression of coronary atherosclerosis in the general population as well as in HIV-infected patients Table .Table 4EFinally, as rosuvastatin has demonstrated to significantly reduce several markers of vascular inflammation and CD4+ and CD8+ T lymphocyte and monocyte activation in HIV-infected subjects on antiretroviral therapy , 53, staAlthough the effects of statins in HIV-infected patients are expected to be of a similar magnitude to that has been seen in the general population, many issues regarding the use of statins in HIV-infected patients are still unclear, and further studies are needed to determine whether statins reduce the number of CV events and mortality in HIV-infected patients.The AIDS Clinical Trial network is currently enrolling in the REPRIEVE  Study, which is a large-scale randomized trial to investigate daily pitavastatin versus placebo for the primary prevention of CV events in PLWHIV. Until the results of such studies specifically conducted in HIV-infected population will be available, we have to relay on guidelines for non-HIV-infected patients for the management of hypercholesterolemia in persons who are living with HIV.For the use of statins in CV disease (CVD) prevention, the European Society of Cardiology and the European Atherosclerosis Society Guidelines, suggest to evaluate the total CV risk of the subjects using European SCORE tables and to identify the LDL-C target for that risk level. For these guidelines, since the response to statin treatment is variable, up-titration to reach that target is mandatory .Differently from European guidelines, the 2013 American College of Cardiology and the American Heart Association guidelines (ACC/AHA) guidelines introduced a new risk calculator, and identified four groups of patients who should be treated with a statin Table  55]. Cu. Cu55]. At maximal recommended dose, the different statins differ in their LDL-C lowering capacity. The ACC/AHA guidelines classify statin doses by three levels of intensity, based on their ability to lower LDL-C levels in the general population Table  55]. On. On55]. Other considerations when deciding about statin therapy include: diabetes mellitus in individual aged less than 40 years or more than 75 years; a family history of premature CVD; elevated lifetime risk of CVD; LDL-C levels of 160 mg/dl or higher; a high sensitivity C-reactive protein level of 2.0 mg/L or higher; a coronary artery calcium score of 300 or higher; an ankle-brachial index below 0.9 .In addition, as HIV-infected patients have been shown to have an increased risk for CVD compared with the general population , the preThe main objection to the ACC/AHA guidelines is that, if generally adopted, these would result in an increased number of patients treated, potentially at considerable costs. Moreover, the new pooled mixed cohorts equation used to assess atherosclerotic CVD risk, has been validated in an American population, different from European countries and requires more careful evaluation if applied in other contexts . In summStatins are generally well tolerated, and serious adverse events are rare . The mosCombination of statins with fibrates may enhance the risk of myopathy. This risk is greater for gemfibrozil, and the association of gemfibrozil with statins should be avoided. The increased risk for myopathy, when combined statins and fibrates seems to be small . The incThe increased risk of diabetes with statin is unclear and high-dose statin are more likely to be associated with diabetes than lower doses . In a raIn patients either unable to achieve optimal LDL-C levels despite statin treatment or intolerant to statin, the availability of new drugs with LDL-C lowering effects may be beneficial for reducing atherosclerotic cardiovascular disease (ASCVD) risk.Ezetimibe is a lipid lowering drug that inhibits the intestinal absorption of cholesterol withouth significant interaction with P-450 cytocromes .Studies on PLWHIV with dyslipidemia evaluated ezetimibe alone or in combination with statins. Ezetimibe alone showed a statistically significant reduction of LDL-cholesterol (ranging from 5.3% to 20.4%) but no significant change in HDL-cholesterol and triglycerides , 66. TheProprotein convertase subtilisin/kexin type 9 (PCSK9) gene, discovered in 2003, encode for a serine protease protein that plays a central role for the regulation of cholesterol metabolism by targeting the LDL receptor (LDLR) for the degradation in the liver . Gain-ofSeveral strategies have been developed to block PCSK9 function including binding of plasma PCSK9 with neutralizing monoclonal antibodies (mAbs) or targeting the intracellular PCSK9 by antisense oligonucleotides or small interfering RNA. Up to date the most studied and clinically advanced approach to PSCK9 inhibition is the use of mAbs.Two mAbs  have been recently approved by the European Medicines Agency for the use in subjects with familial hypercholesterolemia, in patients who failed to achieve acceptable lipid control although an optimal lipid lowering therapy and in those intolerant to statins.Efficacy and tolerability of alirocumab and evolocumab in the general population has been evaluated in different studies, as reported in Table Considering the high efficacy of PCSK9 inhibitors in reducing LDL-C levels when used alone or in combination with a statin, their use in HIV-infected subjects may help to control cholesterol levels and probably to reduce the risk of MACE in this patients’ population.Unfortunately to date, no data on the efficacy of evolocumab and alirocumab among HIV-infected subjects are available. However, a forthcoming randomized trial (NCT02833844) will evaluate safety, tolerability, and efficacy on LDL-C of evolocumab in 450 subjects with HIV and with hyperlipidemia and/or mixed dyslipidemia. Start date is scheduled on May 2017.Isolated hypertriglyceridemia is rare in the setting of PLWHIV on cART in the modern era, the lipid profile usually shows a mixed dyslipidemia , 84. TheFibrates represent the first choice for treatment of hypertriglyceridemia in HIV infected patients. They bind and regulate nuclear receptor peroxisome proliferator activator receptor-α (PPAR- α) and regulate gene expression . FenofibOmega 3 fatty acids have a good safety profile and have been used in HIV-associated dyslipidemia. They demonstrated a reduction of triglycerides ranging from 7% to 38% in a retrospective analysis of 73 patients on PI based regimen vs a non-nucleoside reverse-transcriptase inhibitors (NNRTI) regimen respectively . In threStudies evaluating fibrates and fish oil in mixed dyslipidemia and isolated trigliceridemia are summarized In Table HIV-infected subjects, particularly those treated with antiretroviral therapy, may experience significant accumulation of visceral fat. The increased visceral adiposity has been associated with dyslipidemia and with reductions in growth hormone (GH) secretion –103.The use of tesamorelin, a synthetic analog of human growth hormone-releasing factor, decreases visceral adipose tissue (VAT) and concomitantly reduces tryglicerides, total cholesterol concentration and non-HDL-C among HIV-infected subjects.P < 0.001 for all comparisons).In a study by Falutz et al.  the measIn another study by the same author  the use Similarly a study by Stanley et al. showed that individuals who responded to tesamorelin (defined as a ≥ 8% reduction in VAT) experienced significantly greater improvements in levels of tryglicerides compared to nonresponders .The observed reduction in tryglicerides is probably mediated at least in part by the direct effect of tesamorelin in increasing GH levels and probably by a possible role of VAT reduction itself in decreasing tryglicerides levels .Tesamorelin is usually well tolerated. The most commonly reported adverse events (>10%) were injection site erythema, pruritus, headache and arthralgia .Long-term ART use has been associated with the occurrence of lipodystrophy, a medical condition characterized by an abnormal fat redistribution .Fat redistribution among HIV-infected subjects is usually classified in specific entities: lipoatrophy, lipohypertrophy and mixed syndromes , 111.Lipoatrophy (LA) is the loss of subcutaneous peripheral fat usually at the face, buttocks and limbs , 113 andOn the contrary, lipohypertrophy (LH) that is the accumulation of visceral and central fat in the abdomen, anterior neck, dorsocervical region , trunk and/or breasts , 116, stCardiovascular disease and dyslipidemia among PLWHIV remain nowadays challenging issues. Prevention of CVD risk is the first and essential step of medical intervention on these patients. The lifestyle modification and the education on healthy dietary practices are fundamental tools for reducing CVD risk.Current antiretroviral regimens are easier to take, better tolerated, and more effective than regimens used in the past, therefore optimization of ART in terms of side effects tolerability is essential, since HIV infection requires life-long therapy. The optimal treatment strategies are based on the assumption that not all antiretroviral agents have similar toxicities. PI/ritonavir may cause dyslipidemia and lipodystrophy, while INI have a minimal impact on lipids profile, and not reported evidence of lipodystrophy. There is still much to discover with the introduction of new drugs in clinical practice: dolutegravir, TAF and cobicistat.Statins are the cornerstone of the treatment of hypercholesterolemia. They slow the progression or even promote regression of coronary atherosclerosis and also could exert a wide-reaching anti-inflammatory and immunomodulatory effect. The 2013 ACC/AHA guidelines introduced a new CV risk calculator different from the ESC and EAS Guidelines for the management of dyslipidaemia and identified 4 groups of patients who should be treated with a statin. These guidelines classify statin doses by 3 levels of intensity based on their ability to lower LDL-C levels in the general population. At present, the debate between American and European guidelines is still open and, also considering the independent risk factor represented by HIV, specific guidelines for HIV-infected persons are warranted.Another effective drug for the hypercholesterolemia is ezetimibe that markedly reduces the intestinal absorption of cholesterol. In HIV-infected subjects, ezetimibe already showed to be effective in reducing the total cholesterol and LDL-C levels when used alone or in combination with rosuvastatin. PCSK9 inhibitors, MTP inhibitors, antisense oligonucleotide against apolipoprotein B, adenosine Triphosphate Citrate Lyase Inhibitors are experimental and sometimes promising new classes of drugs for the treatment of hypercholesterolemia.Fibrates represents the first choice for treatment of hypertriglyceridemia in HIV infected patients. Few studies evaluated the use of fibrates and statins in HIV associated dyslipidemia and demonstrated an higher efficacy as reported in the general population. Omega 3 fatty acids have a good safety profile and has been used in HIV-associated dyslipidemia, but their efficacy is limited to patients with a low-moderate dyslipidemia and isolated hypertrigliceridemia. Other drugs for hypertrigliceridemia are: acipimox, that showed a low efficacy; niacin that, in spite of its efficacy can induce insulin resistance and hepatotoxicity; and tesamorelin that has demonstrated a good efficacy in lowering triglycerides and total cholesterol.


The free antiretroviral therapy (ART) program in India still relies on the clinico-immunological monitoring for diagnosis of treatment failure. As the nucleoside reverse transcriptase inhibitor (NRTI) backbone is shared in first- and second-line regimens, accumulation of drug resistant mutations (DRMs) can compromise the efficacy of NRTI. This study was undertaken to describe the pattern of HIV DRMs following immunological monitoring and investigate its impact on the cycling of NRTI between first- and second-line ART.This cross-sectional study was performed at a state-sponsored ART clinic of Pune city in western India between January and June 2016. Consecutive adults receiving first-line ART with immunological failure (IF) were recruited for plasma viral load (PVL) estimation. Randomly selected 80 participants with PVL >1000 copies/mL underwent HIV drug resistance genotyping. Of these, 75 plasma sample were successfully genotyped. The median CD4 count and duration of ART at the time of failure were 98 (IQR: 61.60–153.50) cells/μL and 4.62 (IQR: 3.17–6.15) years, respectively. The prevalence of NRTI, non-NRTI, and major protease inhibitor resistance mutations were 89.30%, 96%, and 1.33%, respectively. Following first-line failure, sequences from 56.67% of individuals indicated low- to high-level resistance to all available NRTI. The proportion of sequences with ≥2 thymidine analogue mutations (TAMs) and ≥3 TAMs were 62.12% and 39.39%, respectively. An average of 1.98 TAMs per sequence were observed following IF as compared to 0.37 TAMs per sequence following targeted PVL monitoring at 12 months of ART from a prior study; this difference was significant (p<0.001).The option of cycling of NRTI analogues between first- and second-line regimens would no longer be effective if individuals are followed-up by immunological monitoring due to accumulation of mutations. Introduction of routine PVL monitoring is a priority for the long-term sustainability of free ART program in India. In India, the free antiretroviral therapy (ART) program has scaled up considerably from eight ART centers in 2004 to over 519 by 2015 –7. The pAs per national guidelines, first-line ART in adults consists of two nucleoside analogue reverse transcriptase inhibitors (NRTI) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) . Followim2000rt system and virological failure was defined as a single HIV-1 PVL of more than 1000 copies/mL [The study was carried out at the state-sponsored "Centre of Excellence" ART clinic of Pune city in western India between January and June 2016. In this cross-sectional study, we recruited consecutive adults with features of IF who were referred for confirmation of failure by PVL estimation. The eligibility criteria were individuals with age >18 years who were initiated on first-line ART as per national guidelines and had an adherence rate of over 95% in the past three months. IF was defined as per WHO definition of clinical and immunological failure, wherein, fall in CD4 cell count to baseline or below and persistent CD4 cell count of less than 100 cells/μL were considered . Estimatopies/mL . Five mipol gene was performed by a previously validated method [https://hivdb.stanford.edu/DR/asi/releaseNotes/#hivdb_ mutationpenaltyHeader). The degree of resistance was categorized into 5 levels based on total penalty score; susceptible (0–9), potential low-level resistance (10–14), low-level resistance (15–29), intermediate resistance (30–59) and high-level resistance (>60). For analysis purpose, two level category was created with a total score of 0–14 was considered as susceptible and a score of >15 was considered resistant. Phylogenetic tree of partial pol gene study sequences along with reference sequences was constructed by the maximum likelihood method based on general time reversible model, with MEGA 6.0 software. The reliability of the branching orders was tested by bootstrap analysis of 1000 replicates.Randomly selected 80 subjects with PVL > 1000 copies/ml underwent HIV drug resistance (DR) genotyping at WHO accreditated HIV drug resistance genotyping laboratory of the National AIDS Research Institute (ICMR), Pune, India. Genotyping of complete protease  and partial reverse transcriptase  region of the d method . FollowiCharacteristics of the study participants were summarized by median and interquartile range (IQR) for continuous variables and by proportion for categorical variables. The proportion of sequences with thymidine analogue mutations  from the individuals with immunological failure in present study was compared with the sequences from a virological failure (VF) group of prior study by Karade et al. [The study was approved by Ethics committee of National AIDS Research Institute and the participants were enrolled after obtaining written informed consent. A total of 56% of individuals with IF underwent treatment switches in the past due to the reasons like adverse drug reactions, drug stock out, and change in the national policy. Importantly, 21 out of 33 patients on TDF based failing regimen had prior exposure to AZT or d4T in past. The proportion of individuals with failure of zidovudine (AZT)- and tenofovir (TDF)-based regimens were 56% and 44%, respectively. Phylogenetic analysis of the partial pol gene sequences showed that 74 sequences clustered with the reference sequence of the Indian HIV-1 subtype C virus; one isolate clustered with subtype A1 . The comparison of demographic features of IF group and VF group is shown in S1 Table.A total of 387 individuals on first-line ART with evidence of immunological failure (IF) reported for PVL testing. Eighty plasma samples, with PVL > 1000 copies/mL were randomly chosen for drug resistance genotyping. Of these, 75 samples, including those from 50 males, were successfully genotyped. The demographic characteristics of the participants at the time of first-line ART failure are summarized in Fig 2. A total of 72% of the sequences indicated the presence of TAMs, with an average of 1.98 TAMs per sequence. The differences in the proportion of sequences with TAM-1 (57.33%) and TAM-2 (49.33%) mutations were not significant . The number of sequences with ≥2 and ≥3 TAMs were 61.3% and 38.67%, respectively. The average TAMs in patients failing AZT based regimen (2.14 TAMs/sequence) was higher as compared to those on TDF based regimen (1.78 TAMs/sequence), however this difference was not significant (p = 0.34). One sequence showed the presence a insertion at codon 69 (T69 insertion) of reverse transcriptase (RT) while another sequence carried the Q151M complex mutations; each of these mutations are known to confer pan-NRTI drug resistance. In addition, another sequence harbored an amino acid deletion at codon 67 of RT. Major PI resistance mutations (M46I and N88S) was observed in a single sequence, whereas four sequences showed accessory mutations Q58E, G73C, T74P, and L10F.The prevalence of NRTI, NNRTI, and major protease inhibitor (PI) resistance mutations following immunological monitoring were 89.30%, 96%, and 1.33%, respectively. M184V (88%) and K103N (46.67%) were the predominant NRTI and NNRTI resistance mutations, respectively. M41L (49.33%) and T215Y (41.30%) were the most common TAMs. The clinically relevant NRTI and NNRTI mutations are shown in .Following first-line ART failure, the susceptibility to various NRTI was ascertained for cycling in second-line ART. Based on the Stanford database HIVDR scoring system, low- to high-levels of resistance to zidovudine (AZT) and tenofovir (TDF) was seen in 65.33% and 49.33% of sequences, respectively. Predicted susceptibility to NRTI in sequences from the present study were compared with our prior study, wherein first-line ART failure was diagnosed by virological monitoring at 12 months of ART [In this study, we report the drug resistance outcomes in individuals with failure of first-line ART, diagnosed as per the current national guidelines. The decade-old National AIDS Control Program still relies on immunological monitoring, wherein six-monthly CD4 cell count measurements are performed, while PVL estimation is only reserved for confirmation of first-line ART failure . In a prThe evolution of TAMs can be limited by early diagnosis of treatment failure. Reynolds et al. compared the HIVDR pattern between a group monitored by 6-monthly PVL testing (VLM group) and another, monitored by 6-monthly CD4 cell count (IM group) . The stuIn the EuroSIDA prospective observational cohort, the rate of accumulation of TAMs in subjects who continued receiving failing regimens was relatively lower  . Unlike 10 copies/mL is indicative of longstanding failure in our study. Lower CD4 cell count and high PVL not only increases the risk of opportunistic infections but also enhances the transmission risk to sexual partners. Therefore, viral load monitoring is essential for early identification of failure. Of note, our study results are limited by the cross-sectional study design and small sample size. In addition, pre-treatment HIVDR reports for the study participants were not available and were presumed to be below 5% [Evolution of resistance is a continuous process. The prohibitive cost limits inclusion of HIV drug resistance testing into the National AIDS Control Program. The clinico-immunological monitoring identification of treatment-failure results in the development of complex DRMs, thereby compromising the NRTI backbone in second-line ART , 26. Undbelow 5% , 28. FurTo conclude, we report extensive HIV DRMs in patients failing first-line ART. Thus, periodic surveillance of HIVDR at the national level is essential to guide the program. The option of cycling of NRTIs between first- and second-line regimens may no longer be effective if individuals are followed-up by immunological monitoring. Finally, access to periodic PVL monitoring and HIVDR testing is a necessity for long-term preservation of the efficacy of current therapeutic options.S1 TableComparison of demographic and clinical characteristics of virological monitoring group (VF) and immunological monitoring group (IF).(DOCX)Click here for additional data file.S2 TableComparison of TAMs in sequences from immunological failure group (IM group) with those retrieved from individuals with virological failure at 12 months of ART (VM group).(DOCX)Click here for additional data file.


This cross-sectional study took place in the integrated tuberculosis (TB) clinic of a large outpatient clinic for HIV-infected patients in Kampala, Uganda. The purpose of this study was to describe the proportion of TB/HIV co-infected adults with virological failure, type and frequency of HIV drug resistance-associated mutations, and the proportion of patients with suboptimal efavirenz levels.HIV-1 plasma viral loads, CD4 cell count measurements, and efavirenz serum concentrations were done in TB/HIV co-infected adults. Genotypic resistance testing was performed in case of confirmed virological failure.After a median time on ART of 6 months, virological failure was found in 22/152 patients (14.5%). Of 147 participants with available efavirenz serum concentration, 26 (17.6%) had at least one value below the reference range, including 20/21 (95.2%) patients with confirmed virological failure. Genotypic resistance testing was available for 16/22 (72.7%) patients, of which 15 (93.8%) had at least one major mutation, most commonly M184V (81.2%) and K103NS (68.8%).We found a high proportion of TB/HIV co-infected patients with virological failure, the majority of which had developed relevant resistance-mutations after a median time on anti-retroviral treatment (ART) of 6 months. Virological monitoring should be prioritized in TB/HIV co-infected patients in resource-limited settings. Mycobacteria tuberculosis and HIV could be attributed to overlapping toxicities and drug–drug interaction [In 2013, the World Health Organization (WHO) reported 47′650 new cases of tuberculosis (TB) in Uganda, making it to one of 22 high-burden TB countries [In resource-limited settings such as Uganda, close treatment monitoring strategies as optimally required for both infections are not readily available for all patients. For financial reasons, virological monitoring of HIV-infected patients on ART has either not been available or is reserved for selected patients , such as patients with diagnosed immunological failure . While CIn the absence of routine or targeted viral load testing, the WHO recommends to monitor ART using CD4 count testing , althougEvidence of reduced morbidity and mortality supports early initiation of ART in TB co-infected patients . AccordiSo far, little information is available on early virological outcomes of TB/HIV co-infected patients on ART, and the development of HIV drug resistance in those with viral failure. The objective of this study was to assess the proportion of TB/HIV co-infected Ugandan patients with virological failure, identify factors potentially associated with treatment failure, and to report type and frequency of HIV drug resistance mutations detected in TB/HIV co-infected patients failing ART.This cross-sectional study was conducted at the integrated TB/HIV clinic of the Infectious Diseases Institute (IDI) in Kampala, Uganda, between April 2013 and 2015. The IDI currently provides care for over 8000 HIV-infected individuals. In the integrated TB clinic [This study was a sub-study of the ongoing “Study on Outcomes related to tuberculosis and HIV drug concentrations in Uganda” (SOUTH study), which investigates the association between TB treatment outcome and serum concentrations of anti-TB drugs in TB/HIV co-infected Ugandan adults . Participants included in the study were HIV-infected adults of 18 years and above, receiving treatment with rifampicin, isoniazid, pyrazinamide, ethambutol for 8 weeks, followed by 16 weeks of rifampicin/isoniazid for newly diagnosed pulmonary TB . EfavireHIV type 1 plasma viral load measurements were performed as soon as a patient had been on ART for at least 6 months, accompanied by simultaneously measured CD4 cell count. Viral load measurements  and CD4 cell counts  were performed at the Makerere-University-John-Hopkins-University (MUJHU) CORE laboratory certified by the College of American Pathologists, located at the IDI. For patients receiving efavirenz-based ART, efavirenz serum concentrations were measured on-site, 9–15 h post-dosing using a validated ultra-violet high-performance liquid chromatography (UV-HPLC) method at week 8 and 24 of TB treatment. Patients with confirmed virological failure received genotypic drug resistance testing performed at the Ugandan Virus Research Institute/Medical Research Council (UVRI/MRC) in Entebbe, Uganda, (Method: PCR gel electrophoresis and purification (QIAquick PCR purification kit), sequencing , genetic analysis , base-called sequences , quality assurance , and assigning of drug resistance mutations (submission of sequences to Stanford HIVdb Program).Virological failure was defined as one HIV-1 plasma viral load >1000 copies/ml or two consecutive viral loads >400 copies/ml within three months. Favorable outcome of TB treatment was defined as fulfilling the WHO criteria of either cured or completed treatment . HistoryDuring the study period, one hundred and fifty-two individuals were enrolled in this study. The median age was 34 years (interquartile range (IQR): 28–39) and 58.6% of the study participants were male. The majority was ART-naïve at time of TB diagnosis  and they were initiated on efavirenz-based ART two to four weeks after starting TB treatment. The median CD4 cell count at time of viral load measurement was 285 cells/µl (IQR: 150–453).The most common ART regimen at time of viral load measurement consisted of tenofovir, lamivudine and efavirenz , followed by zidovudine, lamivudine and efavirenz . Only four patients (2.6%) were on second-line treatment with tenofovir, lamivudine and either ritonavir-boosted atazanavir or ritonavir-boosted lopinavir. Of all patients enrolled, 30 (19.7%) had previously substituted at least one antiretroviral drug, mainly due to TB co-infection.10 of 4.6 copies/ml (IQR: 4.0–5.3). Of patients with virological failure, 11 (50%) had been ART-naïve at TB diagnosis. Table Viral load measurements were performed after a median time on ART of 6 months IQR: 5.5–12). Virological failure was found in 22/152 (14.5%) patients, with a median viral load log2. ViroloGenerally, TB treatment outcome was favorable in our study population with 142 (93.4%) patients being cured or completed treatment. However, a lower proportion of patients with virological failure had a favorable TB treatment outcome (77.3%) as compared to patients with viral suppression (96.2%) .A total of 148 participants were on efavirenz-based ART, of which 147 had available efavirenz serum concentration. Of these, 26 (17.7%) had at least one efavirenz serum concentration below the reference range of 1 mg/l; a significantly higher proportion of patients with confirmed virological failure (95.2%) had a serum concentration below the reference range as compared to patients with viral suppression.Of the 22 patients with virological failure, 16 (72.7%) underwent genotypic resistance testing. The remaining 6 patients were either lost-to-follow-up (2 patients), had died (2 patients), or were switched to second-line treatment before resistance testing could be done (2 patients). HIV subtype distribution of these 16 patients was as follows: subtype A, C, D and recombinant were 3, 1, 3, and 8 patients respectively. Among recombinant HIV strains we found 5 CRF and 3 A/D. As shown in Table Among our population of Ugandan TB/HIV co-infected adults on ART and TB treatment we found a high proportion (14.5%) of patients with virological failure after a median time on ART of 6 months. A similarly high proportion of treatment failure was previously observed among TB/HIV co-infected patients from India , 16. HowThe majority of patients with virological failure on efavirenz-based ART had at least one efavirenz serum concentration below reference range during concomitant TB treatment. Efavirenz levels below reference range are a risk factor for virological failure and the development of resistance-associated mutations . AlthougReasons for poor adherence are diverse in TB/HIV co-infected patients and include large pill burden and significant side effects, as well as factors affecting non-TB-infected HIV-positive patients such as stigma or disbelief. As TB in sub-Saharan Africa disproportionately affects the economically most disadvantaged members of society , additioOnly 50% of patients with virological failure also had immunologic failure. Thus, in the absence of virological monitoring, treatment failure would not have been detected in these patients. Patients with undetected treatment failure are at risk of further accumulation of resistance mutations, which complicates future treatment in a setting with limited antiretroviral drug options and may contribute to the transmission of drug resistant viruses to partners. In our study population, the majority of patients with virological failure had already developed relevant resistance mutations after a median time on ART of 6 months. Among patients with available data on HIV drug resistance, 15/16 (93.8%) required switching to second-line drugs due to resistance-associated mutations. Most strikingly, the majority of the patients had developed two class drug resistance to both NNRTI and NRTI, which greatly limits optimal treatment choices in this setting. M184 V and K103NS were the most prevalent mutations found, reflecting prior treatment with lamivudine, efavirenz or nevirapine. Major PI mutations were not observed in any of the participants.Partly, our study findings are limited by the fact that HIV drug resistance tests were not performed before the initiation ART and, therefore, information on transmitted drug resistance was not available. However, so far pre-treatment HIV drug resistance seems to be low in Uganda .In conclusion, based on our study finding of a high proportion of TB/HIV co-infected patients with virological failure and selection of relevant resistance mutations after only 6 months on ART, we recommend that virological monitoring should be prioritized in TB/HIV co-infected patients in resource-limited settings. In addition, further efforts are required to address specific adherence challenges in TB/HIV co-infected patients.