There is paucity of data on quality of life as a dimension of treatment outcome among Visceral Leishmaniasis and HIV coinfected patients. This study sought to explore perceived quality of life among Visceral Leishmaniasis and HIV coinfected male migrant workers in Northwest Ethiopia.Twenty Visceral Leishmaniasis and HIV coinfected study participants took part in the in-depth interviews at Visceral Leishmaniasis and HIV treatment centers. Ten participants were on antiretroviral treatment (ART) and the remaining 10 have not yet started ART. All interviews were recorded, transcribed and translated for analysis. Data were analyzed by qualitative content analysis using Open Code software version 3.4.Participants reported on four aspects of quality of life: liveability of the environment, utility of life, life ability of a person and appreciation of life. Respondents living environment, therapeutic side effects of Visceral Leishmaniasis drugs, poverty and stigma negatively affected their quality of life. On the contrary, good treatment response and financial security were reported to positively affect their quality of life.Challenges related to the living environment, financial limitations and sub-optimal response of Visceral Leishmaniasis drug and relapse of Visceral Leishmaniasis disease are factors most negatively affecting the quality of life of Visceral Leishmaniasis and HIV coinfected patients. Micro-financing and other socio-economical support programs should be launched to assist the unemployed males migrating to Visceral Leishmaniasis endemic and relatively higher HIV prevalent areas to work as daily laborers. HIV prevention programs in HIV positive-living counseling programs should target such high risk migrant workers in the endemic areas. Human immunodeficiency virus (HIV) and Visceral Leishmaniasis  coinfection reported in 35 countries , 2, amonVL and HIV coinfection are associated with special therapeutic challenges. VL-HIV coinfected patients are at higher risk of relapse and death. Furthermore, VL adversely affects the response to antiretroviral therapy (ART) , 6. In EMany studies have provided important information on the correlates of health related quality of life (HRQoL) during HIV infection. Several studies have documented significant improvements in QoL during ART –10. TherAn in-depth qualitative, phenomenological study design was selected to carry out searching of the lived experience and perceptions of the study subjects on the quality of life of VL-HIV coinfected male patients that were receiving VL treatment.The study was carried out at three different sites found in Northwest Ethiopia. The first site was Abdrafi inpatient kala-azar treatment center located in Abdrafi; at this health center medical services are provided for patients with Leishmaniasis, VL-HIV coinfection and snake bite. The second site was Kala-azar Treatment and Research Center found in the University of Gondar Hospital located in Gondar; at this center both outpatient and inpatient medical services are provided for patients with Leishmaniasis and VL-HIV coinfection in addition to the comprehensive medical service from other units in the University of Gondar Hospital. The third site was Kahsay Aberra Hospital located in Humera kala-azar treatment center; at this center both outpatient and inpatient medical services are provided for patients with Leishmaniasis, VL-HIV coinfection and many other hospital level services. Study participants come from different parts of kala-azar endemic areas with a variety of cultural background in Northwest Ethiopia. As the typical patient approach procedure, when the patients come to the clinic, the physicians and the health officers will do clinical and laboratory examinations to diagnose the patients for kala-azar, if patients are found to be positive for VL they will further screen them for HIV. This allows the health workers to select the appropriate treatment for VL-HIV coinfection.The study included twenty VL-HIV coinfected male patients who were attending VL treatment. Newly diagnosed VL-HIV coinfected patients who already started ART and who didn’t start ART were included in this study. We distributed invitation letters to approach the study participants at kala-azar treatment centers of the selected health facilities in the study area. A purposive sample of 20 study participants, ten patients who already started ART and the remaining ten patients didn’t start ART, participated in the study. Study participants had not been evaluated for quality of life before this study. Individuals who were seriously sick and mentally disabled were excluded.The data collection method was in-depth semi-structured interviews. After securing written informed consent, a topic guide was used as a prompt for questioning. The key consideration for influencing the direction of each interview was the participant’s response to questions in terms of their individual experiences. The principal investigator (PI) conducted the face-to-face in-depth interviews using semi-structured guide in venues suitable for the participants. The guide was developed in English and translated in to Amharic  for all participants. Interviews were recorded using audio recorder devise in order to capture all information provided by the interviewee.The interview was started by couple of questions prepared to create rapport with the study participants. These questions focus on the life experiences as a migrant worker and challenges they faced when they are diagnosed with VL-HIV coinfection. After we created a rapport, the theme of quality of life issues was introduced in subsequent interview of persons living with VL-HIV coinfection. The interviewer probed for any changes in personal values, responses for treatments and goals and how they are related to quality of life.The PI had continued interviewing participants until no new information is provided from additional interviews . Upon completion of each interview and based on the recorded audio the PI developed a detailed transcription that captures all the discussion. These texts and the emerging themes identified during the course of the interviews were confirmed by the coauthors and issues were addressed. All the interviews were transcribed and prepared for coding and thematic analysis. The typed data were analyzed by qualitative content analysis using the Open Code software version 3.4 . The Open Code software is used as a tool for classifying and sorting qualitative information.The investigators scrutinized transcripts were read multiple times in order to get general sense of the content. An inductive qualitative content analysis method was used to analyze the data. A coding framework was developed based on the emerging themes. Emergent categories and themes were identified based on meticulous and systematic reading and coding of the transcripts. Codes and sub-codes were refined during the analysis. This was done by the PI and reviewed by the coauthors.Among the twenty patients included in the study, ten patients were started taking antiretroviral (ARV) drugs in addition to the Visceral Leishmaniasis (VL) drugs during interview. The remaining ten patients have not yet started taking ARV drugs but were taking VL treatment. All of the study participants were male migrant workers. The age range of participants was from 25 to 52 years. Emergent categories and themes were identified from the interviews, including “Liveability of the environment” as indicators of QoL; “Utility of life”, covers responses of life expectations/goals; “Life ability”, covering responses to VL and HIV treatments, stigma, stress and VL relapse and appreciation of life.Quality of life was discussed in terms of wellbeing and happiness influenced by good health, having money, good living environment, good social relations and emotional wellbeing. All of the study participants (taking ART and not taking ART) interviewed defined QoL in a way similar to World Health Organization (WHO) definition of health as “a state of complete physical, mental and social wellbeing and not merely absence of disease or infirmity” .One 51 year-old man, taking both VL and ARV drugs said “QoL is about being healthy, having good energy and enough money.” A 42 year-old man, taking both VL and ARV drugs remarked “QoL is when one has health, access to VL treatment centers and money. If I have money and access to VL treatment center, I am able to treat my VL relapse immediately; my QoL is good”. A 39 year-old man, taking only VL drug and not in ART said “QoL is about not working in hot areas (low lands) and having work in cold areas (high lands), having shelter”. A 33 year-old man, taking both VL and ARV drugs said “QoL is about having money, not doing laborious work, free from any substance use or abuse such as chewing khat, smoking cigarette and drinking alcohol and not being coinfected by VL”. Another 29 year-old man, taking only VL drug and not in ART said “It’s about being cured from VL, able to create my own business and earn money and marrying a woman and have children”.The majority  of the study participants in both groups mentioned availability of money is very much vital for their wellbeing and hence a good QoL, and for example “for me after I finished VL treatment, I don’t have money for transport to go back to my residence. To cover my daily expenses I need to have money”  and “I need money to pay my house rent, for food and to buy clothes that are vital for sustaining my life” . One 32 year-old man, taking both VL and ARV drugs said that “I am very much worried about my future life after I am discharged from this VL treatment center. Unlike previous times I don’t have enough energy to work as a daily laborer in hot areas (low lands) because VL infection severely weakened my body. On the other hand, in order to do my own job, I don’t have enough money. I am very much worried about how to get money for my daily subsistence. It is very much difficult to be happy and lead good QoL when you have no money”.All of the respondents in both groups stated that good health and money were crucial to their wellbeing and QoL. Most of the participants were migrant daily laborers. They were more frank when discussing money as a source of wellbeing. For instance, one 34 year-old migrant daily laborer resided in May-kadra district who are taking only VL drug and not in ART said that “my choice of living in May-kadra is because there is job opportunity and I am able to earn money” and also one 33 year-old migrant daily laborer residing in Humera district who are taking both VL and ARV drugs stated “In order to sustain my income, I am working laborious work in very hot area of Humera districts”.Almost all  interviewees in both groups highlighted living environment as a cornerstone of their not wellbeing and QoL, for example “I have resided and spent many years in very hot area because I can be easily employed as a daily laborer in large farms and I can generate money easily. It is not suitable for health because there are diseases like malaria and VL”  and “I am living in a hot and VL disease prevalent area. For this reason I am not happy in my living environment and withstanding all those problems I will continue working as a daily laborer to sustain my income” . One 29 year-old man taking only VL drugs and not in ART said “I am working as a daily laborer moving from one hot area to the other hot area in order to generate money for my daily expenses. Those areas I have visited were very hot and were not suitable for health because there are different diseases like malaria, VL and diarrheal diseases”.Lack of happiness due to living environment was reported by majority  of the respondents in both groups. For instance, one 39 year-old man, taking only VL drugs and not in ART said that he is fade up of working as daily laborer in “berha”, translated as “very hot areas or low lands”. When asked what exactly he meant by this, he explained that these areas are extremely hot and there are different diseases like VL. Therefore, working in those areas were made me coinfected with VL and it makes me very much weak.Social relationships including support from immediate family reported by few (2 patients or 10%) of the respondents in both groups as a key to their wellbeing, for example, “I have supportive family, my mother’s wellbeing and successful friends around me makes me happy”  and “a good relationship with my wife and the care I get from my brother makes me happy” .Emotional stability was a concern among a few (1 patient or 5%) of those interviewed. A 45 year-old man, taking only VL drugs and not in ART described QoL as “Living the life without worries is having good QoL”. As happiness was stated by all of the participants, we asked them further what was meant by happiness for VL-HIV coinfected patient. Happiness was seen as indicator of QoL. The main factors remarked as a source of happiness were to get cured from VL disease and the free treatment they got from the treatment facilities. The other factors mentioned as a source of happiness included financial wellbeing. These findings were consistent across all ages and for both groups (with and without ART) of the participant.Almost all  of the study participants in both groups clearly mentioned that recovering from VL disease and the treatment centers where they have received care were the source of their happiness. One 25 year-old man taking only VL drugs and not in ART said “my source of happiness depends on being cured from VL disease”. Another 34 year-old man, taking only VL drugs and not in ART stated that “the only way to get back my happiness depends on being cured from VL disease”. A 33 year-old man, taking both VL and ARV drugs remarked “my happiness entirely depends on recovering from VL disease. I am also very much happy by free treatment that I got from this treatment center”. One 41 year-old man, taking both VL and ARV drugs said that “My source of happiness entirely depends on the fact that I am cured from VL disease and the support I got from the treatment center. In the last 5 years I had experienced eleven times VL relapse and in all those relapses this treatment center was giving me free treatment”.All (20 patients or 100%) of the participants in both groups were mentioned lack of economical wellbeing as a major contributor to their unhappiness. According to one 34 year-old man, taking only VL drugs and not in ART said “In order to lead my life properly I need money and money is everything. I don’t have money to cover my daily expenses. If I don’t get money to cover the cost of a transport from the treatment center to my home town then I will be a beggar”. A 42 year-old man, taking both VL and ARV drugs said “money is a source of my happiness. For instance, if I didn’t have money I wouldn’t reach here to follow my treatment. Hence, when I have money in my pocket I do have a better happiness. Currently I don’t have money and I feel very much angry”. A 51 year-old man, taking both VL and ARV drugs said “I feel very much angry when I have no money; I am not a happy person because I don’t have money to pay for house rent and to buy my daily food consumption”.Majority  of the participants in both groups were given Liposomal amphotricine B  and some  received a combination of AmBisome with oral Miltefosine for VL treatment. Most  of the participants in both groups who received only AmBisome reported side effects. Those who had side effects said that they cleared within a couple of days and that they felt much better. A 51 year-old man, taking both AmBisome and ARV drugs said “the first few days may be four to five days were bad, I was unconscious for the first day, the next 3 to 4 days I had experienced severe sweating, abdominal cramp, constipation, sense of burns around injection areas and series of vomiting and later stabilized”. Another 25 year-old man, taking only AmBisome and not in ART also stated “the first couple of days were bad, I experienced series of vomiting that included blood, lower back pain, variability of body temperature and loss of appetite and then after few days these were ceased”.Two third  of the participants in both groups who received a combination of treatment were also reported side effects, for example, “After I have taken VL drugs, I experienced stomachache, constipation, feeling pain during urination, loss of appetite and severe lower back pain” , and “the side effects that I experienced because of VL drugs are diarrheal disease and loss of appetite and whenever I took Miltefosine without eating food I felt stomachache and vomiting” .A 45 year-old man who is in ART and he had been experienced seven times VL relapses in the past four years said “Among all side effects of VL treatments that I experienced during my VL relapse times; my second time VL relapse treatment were very much severe. The drug I had taken during this time was sodium stibogluconate (SSG). After nine days of taking SSG I experienced that around two liters of blood came out from my mouth and nose and later I quit the drug and the physician changed it to AmBisome”.Some of the participants in ART group reported a reduction in therapeutic response of VL treatment and this results high rate of relapse, for example, “I have experienced six times relapse. In most cases the VL relapse occurs when I am starved and when I am engaged in laborious works in very hot areas (low lands)”  and “Usually my VL relapses when I am engaged in laborious work in very hot areas” . A 41 year-old man, taking both VL and ARV drugs remarked “In the last five years I had experienced 11 times VL relapse because of this reason I couldn’t manage to do work and able to generate money for my daily expenses”.Most  of the participants who are in ART group reported minor side effects of ARV drug and these side effects were cleared within few days and then they felt much better. Those who had these side effects of ARV drug perceived the side effects as very minor compared to the benefits of taking ARV: “The first few days may be 2 or 3 days were bad, I felt sleep disorder and dizziness and later stabilized” . Another 33 year-old man, taking both VL and ARV drugs said “For the eight days since I started ARV, I experienced bad dreams and sleep disorder then after eight days these feelings were ceased”. One 29 year-old man, taking both VL and ARV drugs stated “The first eight days were bad; I had sleep disturbance and terrible dreams which later ceased. Sometimes I felt headache after I have taken ARV drug”.Almost all  of participants who were not in ART have high interest to start taking ARV drugs. The reason of not starting ARV drugs was residence of the participant. All (10 patients or 100%) of the participants who have not in ART are migrated from their home town to be employed as daily laborer in study areas. Therefore, after they completed VL treatments they will be linked to ART centers that are found in their permanent residence or home town. A 34 year-old man, taking only VL drugs and not in ART said “After I completed my VL treatment, I will start ARV drug in May-kadra health center which is found in my home town”. Another 36 year-old man, taking only VL drugs and not in ART stated “Till now I didn’t start ARV drug. The reason for this is I planned to start the drug in my home town ART center”. One 42 year-old migrant daily laborer, taking only VL drugs and not in ART said “I have an interest to start ARV drug but I fear to communicate my HIV status to my wife. The reason for this is my wife is very rigid and I am in deep fear that she will not accept me. My last option will be requesting divorce without telling my HIV status. If it is successful I will start the drug otherwise I will not start it”.The majority  of the study participants who are in ART reported stigmatization due to their HIV status. Some  respondent’s who are in ART seemed to have convinced themselves about their HIV infection and didn’t worry about what other people said or thought of them. A 42 year-old man, taking both VL and ARV drugs said “In my village there is a trend of disgracing a person when he is HIV infected. Because of this reason no one knows about my HIV status and I will keep it secret from my family, friends and the community at large”. Another 39 year-old man, taking both VL and ARV drugs stated “After I told my HIV status to my best friend he refused to eat with me”. Similarly, one 32 year-old man, taking both VL and ARV drugs reported that “After I disclose my HIV status to my best friend and his wife, she refused to eat with me”.Many of the respondents were migrant daily laborers and they are supposed to work in group in big farm lands – thus making clear their HIV status makes them discriminated by the group. One 42 year-old man, taking both VL and ARV drugs said “I used to work in a group as a daily laborer in Abdrafi farm lands. Among the group one of my friends knew about my HIV status. One day in the middle of the day I felt tired and decided to have nap. During this time my friend told the group about my HIV status and then the group refused to eat and work together with me”.A few  respondent’s who are in ART reported no sense of stigma. One 45 year-old man, taking both VL and ARV drugs said “some people gave me an advice not to take ARV drugs in front of the people but I don’t mind if people know. I always share my experience and how good my life is with the HIV treatment. I encourage people whom I knew to know their HIV status and to act accordingly”. A 41 year-old man, taking both VL and ARV drugs remarked “I don’t care if people know my HIV status. I don’t bother about what other people say about me”.All (20 patients or 100%) of the participants in both group interviewed reported that they were fearful, shocked and worried at the time of VL and HIV concurrent diagnosis. Though, they got support from health care providers. A 34 year-old man, taking only VL drugs and not in ART described his reaction after he was tested VL and HIV coinfection “I was very much depressed and stressed. I thought I was going to die”. Another 41 year-old man, taking both VL and ARV drugs who had been experienced eleven times relapse said “I am depressed and worried about my future life. The multiple VL relapses that I have experienced make me desperate. Many times I felt angry and stressed”. One 25 year-old man, taking only VL drugs and not in ART said “The first couple of weeks were bad, I felt stress and fear to die and later I stabilized quickly after VL and HIV treatment was started”. Participants expressed anxiety about house rent and daily subsistence “Currently I have no money and enough energy to work as a daily laborer; these are my major problems,” remarked a 51 year-old man, taking both VL and ARV drugs.Over a half (12 patients or 60%) of the participants in both groups were hopeful and have set goals for their future life. There were similarities in the desire expressed by the majority of hopeful respondents regarding their wish to gain enough money for creating their own job. The participants’ future plans included relocating their living environment to cold areas, opening mini shop to sustain their income, building their own homes, getting married for those that were unmarried and having children. Plans were explained:“I hope to make more money and opens my own hotel” , “I would like to relocate from very hot area to cold area like Gondar town; I would also like to be a merchant and get married to have children” , “I would like to make more money and relocate to cold areas; I would also open mini shop to sustain my income and I will marry a woman of the same status” , “I would like to change my profession, build home in the outskirt of the town, and buy cattle, sheep and hens so that I will get non-laborious work” .A few  interviewees who are in ART have changed habits such as chewing khat and drinking alcohols because of frequent relapses of VL, and put increased focus on planning for their future how not to be coinfected with VL again. “My VL relapses were occurred when I consecutively engaged in substance use/abuse like khat chewing and drinking alcohol. Therefore, in order to prevent VL relapse I have stopped khat chewing and drinking alcohol” (39 year-old man who was taking both VL and ARV drugs and experienced six times relapse), “I used to drink alcohol and smoke cigarette. I stopped these activities since I started treatment. I live my life free from any substance use/abuse to prevent VL relapse” .Some  of the study participants in both groups were not hopeful about their future, for example, “My future is dark because I don’t have enough energy to work as a daily laborer. I am also desperate for not establishing family” , “I don’t have future because if I wasn’t infected with HIV, I would have married and have children” . One 41 year-old man who was taking both VL and ARV drugs and experienced eleven times VL relapse said “There is no future for me because the frequent relapse of VL makes me very much week and I have no money to lead my life and to establish family”.QoL by VL-HIV coinfected patients was commonly explained by both groups as being cured from VL disease, change living environment from very hot areas to cold area town and opening mini shop to sustain their income. One 34 year-old man, taking only VL drugs and not in ART said “when coinfected patient cured from VL disease, they have no problems and whatever they set out to do comes out as desired like building home and opening mini shop to sustain their income”. One 51 year-old man who was taking both VL and ARV drugs and experienced six times relapse explain “It’s when one prevents VL relapse, suffers no illness and has mini shop or micro business to earn money for their daily subsistence like eat, drink, and no worries”. Another 33 year-old man, taking both VL and ARV drugs said “It’s about curing from VL disease, when you are healthy and living in cold areas. In addition, when you have income generating means like mini shop for making your basic needs satisfied”.This study showed that the VL-HIV coinfected patients have to overcome poor QoL; and, special emphasis should be given for the complex challenges existing in the treatment and care of VL-HIV coinfected patients. The findings of this research article were framed in accordance with the Ruut Veenhoven model of “four qualities of life” . ParticiLiving environment was mentioned as indicator of poor QoL by our study participants. Living in very hot lowland areas was a source of VL infection and hence results a poor QoL, all of the participants reporting that their VL infection or relapse were because of their living environment. Our finding was supported by the eco-epidemiology study of VL in Ethiopia , the HumThe study participants in this study thoroughly discussed their quality of life. They have mentioned the most important aspects in their lives and that have been related to their experience of living with VL-HIV coinfection. The ability to work and earn money to sustain their daily subsistence was described as a major component of their quality of life. Qualitative studies on wellbeing of HIV infected patients in some of the developing countries including Ethiopia, mentioned similar theme and determinants of wellbeing found in our study group. Food, money, shelter, health, family relations, children and education were commonly considered important for wellbeing in population groups , 15.The availability of VL treatment has had a significant impact on QoL of coinfected patients. Most of the patients who received AmBisome and combination with oral Milefosine for VL treatment reported slight side effects. Those who had experienced side effects said that they got relief within a couple of days and that they felt much better. Some of the participants who had a history of VL reported that a reduction therapeutic response of VL treatment and this results high rates of relapses. These findings were supported by other quantitative studies that are conducted on long term effectiveness and treatment outcomes of VL-HIV coinfected patients treated with AmBisome . The VL-Access to the VL-HIV treatment centers has had a contribution to the positive changes in livelihoods of some VL-HIV coinfected patients and it results hopefulness for their future. There were similarities in the desire expressed by the majority of hopeful respondents to gain money for opening mini shop to sustain their income and changing their living environment to non VL endemic areas. This finding is supported by a study from South Africa that elaborates in further details on how HIV patients regained health and social relations while in care . WhereasMajority of the study participants’ who were in ART demonstrate that they continue to quietly suffer from stigmatization, stress, poverty, uncertainty about the future and an inability to make known their HIV status. Participants reported experiences of varying degrees of stigma. These results are similar to those of other studies in both developing countries , 19 and The limitation of this study is clearly stated by the following statements. All interviews were conducted by the PI and this may have introduced some bias however tape record were played for the study participants and confirmed by their signature and transcripts were also reviewed by colleagues. The present study participants were only male migrant daily laborers this may also introduce some bias. The reason for not including female sex was the difficulty of finding infected female migrant daily laborers. Interviews were tape recorded and this may also have introduced some bias because some of the interviewees were not comfortable with the audio recorder practice due to stigma and non disclosure of the status.This study highlights the complexities and multi-dimensional nature of QoL and provided the challenges and concerns faced by those VL-HIV coinfected male patients in an African setting. Challenges of living environment and therapeutic response of VL treatment are factors that most negatively affect the QoL of VL-HIV coinfected patients. Engaging the unemployed males who are desperately migrating to VL endemic and high HIV prevalent areas for job with micro-finance programs and giving technical support to help them create their own job will not only improve the quality of life of the already VL-HIV coinfected individuals but also will alter the transmission dynamics of both HIV and VL. It is possible to plan control programs specific to the endemic areas if the unpredictable nature of the migration dynamics is not interfering with the policy and programmatic planning and intervention. Clinical trials aiming at reducing side effects and improving efficacy should be encouraged. HIV prevention programs and HIV positive-living counseling programs should target migrant workers to VL endemic areas in the country.Despite the free treatment of VL-HIV coinfected patients provided by the treatment facilities found in Northwest Ethiopia, those who faced a frequent relapse of VL experienced life disruption. Although some participants spoke hope for the future, there are fundamental factors that cause adverse impact on QoL of VL-HIV coinfected patients. These factors were relapse of VL, stress, stigma, poverty and depression. These factors need to be targeted and addressed when managing these patients.


A substantial number of patients with HIV in South Africa have failed first-line antiretroviral therapy (ART). Although individual predictors of first-line ART failure have been identified, few studies in resource-limited settings have been large enough for predictive modelling. Understanding the absolute risk of first-line failure is useful for patient monitoring and for effectively targeting limited resources for second-line ART. We developed a predictive model to identify patients at the greatest risk of virologic failure on first-line ART, and to estimate the proportion of patients needing second-line ART over five years on treatment.A cohort of patients aged ≥18 years from nine South African HIV clinics on first-line ART for at least six months were included. Viral load measurements and baseline predictors were obtained from medical records. We used stepwise selection of predictors in accelerated failure-time models to predict virologic failure on first-line ART . Multiple imputations were used to assign missing baseline variables. The final model was selected using internal-external cross-validation maximizing model calibration at five years on ART, and model discrimination, measured using Harrell's C-statistic. Model covariates were used to create a predictive score for risk group of ART failure.A total of 72,181 patients were included in the analysis, with an average of 21.5 months (IQR: 8.8–41.5) of follow-up time on first-line ART. The final predictive model had a Weibull distribution and the final predictors of virologic failure were men of all ages, young women, nevirapine use in first-line regimen, low baseline CD4 count, high mean corpuscular volume, low haemoglobin, history of TB and missed visits during the first six months on ART. About 24.4% of patients in the highest quintile and 9.4% of patients in the lowest quintile of risk were predicted to experience treatment failure over five years on ART.Age, sex, CD4 count and having any missed visits during the first six months on ART were the strongest predictors of ART failure. The predictive model identified patients at high risk of failure, and the predicted failure rates over five years closely reflected actual rates of failure. South Africa has the world's largest HIV epidemic, with approximately 6.8 million people living with HIV in 2014 , yet fewThe aims of this study are to estimate absolute first-line ART failure risk over five years on treatment as a function of a baseline profile of demographic, clinical and immunologic factors and their interactions, and to develop a predictive model that can be applied to other South African clinic populations, giving estimates of proportion of patients needing second-line ART over time. At the population level, this model can provide long-term estimates of the need for second-line ART in South Africa over five years for patients who remain in care, given characteristics of the population beginning ART. At the individual level, this model provides risk groups for treatment failure for patients who begin treatment, which can be used to identify patients at the highest risk. Identifying high-risk patients allows for targeted adherence interventions and counselling, ideally avoiding treatment failure and the need for second-line, or potentially third-line ART, and more powerful drugs.We conducted an observational cohort study using routinely collected medical record data from the Right to Care clinical HIV cohort, which includes patients who had initiated treatment between 2004 and 2013 from nine HIV clinics in South Africa that follow national treatment guidelines . Clinics used an electronic medical record system that records basic information on demographics , clinical information , date of visits, lab results, diagnoses and HIV treatment. We labelled each clinic letter A through I. Retrospective analysis of the Right to Care cohort was approved by the Human Research Ethics Committee of the University of the Witwatersrand. Boston University provided permission for analysis of de-identified data.We included treatment-naïve adult patients (aged ≥18 years) initiating standard first-line HIV treatment who had received at least six months of ART. A standard first-line regimen was defined as two nucleoside reverse transcriptase inhibitors (NRTIs) (stavudine (d4T), zidovudine (AZT) or tenofovir (TDF) plus lamivudine (3TC) or emtricitabine (FTC)) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) (either efavirenz (EFV) or nevirapine (NVP)).Predictor variables came from clinic data at ART initiation, including age, sex, year of ART initiation, clinic, CD4 count, World Health Organization (WHO) stage, body mass index (BMI), haemoglobin, total lymphocytes, mean corpuscular volume (MCV), red blood cell count (RBC), creatinine, creatinine clearance, alanine transaminase (ALT), aspartate transaminase (AST), blood pressure, history of tuberculosis, peripheral neuropathy, NRTIs and NNRTI in first-line regimen, history of alcohol and history of smoking. Having any missed visits by more than seven days prior to our start of follow-up at six months on ART was also included as a predictor. Baseline lab measures were taken from the test closest to ART initiation, using values 90 days before to seven days after ART initiation.Follow-up time began at six months after ART initiation at the time of the first scheduled viral load. If patients had an earlier viral load measurement (at three to six months on ART), follow-up time began at the time of viral load measurement for these individuals. Our primary outcome was virologic failure after first-line initiation. Date of virologic failure was defined as the date of the second of the two consecutive viral load measurements >1000 copies/mL. Person-time ended on the occurrence of any of the following: first-line treatment failure, switch to second-line ART (defined as switch to a protease inhibitor (PI)-based regimen plus addition of at least one new NRTI), loss to follow-up, death, transfer to another clinic or date of dataset closure (April 2014). Loss to follow-up was defined as not visiting the clinic within six months of closure of the study, and the date of loss to follow-up was the date of the last visit.Distributions of all baseline variables were examined in summary and stratified by the year of ART initiation. The overall failure rate and rates by clinic were examined with Kaplan-Meier curves. The predictive model for ART failure was developed using validation of accelerated failure-time survival models, since these parametric models allow for direct calculation of predicted probabilities of survival at specific time points ,12. Firsp<0.2, and later evaluated for predictive value. Biologically plausible multiplicative interactions between predictors with p<0.2 were considered in final candidate models. Multiple imputation was used for missing predictor variable data ^(1/s)}, where t=time and s=the scale parameter. We used the summation of beta estimates for each individual to determine the relative likelihood of failure, and created risk groups based on quintiles of these scores. To simplify risk group calculation for use in clinics, we transformed the beta estimates for all predictors by setting the lowest risk group as the reference category, removing the intercept (baseline hazard), multiplying each beta estimate by 10 and rounding to the nearest digit. This transformation created a whole number for each predictor that would allow summation of all risk factors to calculate a risk score.Scoring for a predicted risk group was directly generated from beta estimates of the final predictive model. A survival estimate can be calculated from the Weibull model at any time point based on a transformation of the summation of beta estimates First-line failure could not occur if death or switch to second-line ART occurred first. The impact of these competing risks was assessed graphically . PatientThere were 72,181 adult patients who initiated a standard first-line ART regimen after 2003, and had at least six months of follow-up. Most were aged between 30 and 39 years (43.7%), female (65.0%) and had a first-line ART regimen containing d4T (60.0%) and EFV (86.9%). Follow-up time ended in treatment failure for 9.5% of patients, death for 4.8%, switch to second-line ART for 3.5%, loss to follow-up for 19.7%, clinic transfer for 25.1% and censoring for the remaining 37.5% at the end of the study period. Median follow-up time was 21.5 months (IQR: 8.8–41.5). After 5.5 years on treatment, >15% of subjects experienced first-line treatment failure. The failure rate was similar in all clinics except for Clinic E, which showed a much higher rate, and Clinic I, which had a lower rate.3 in 2004, 12.4% in 2013) and fewer underweight patients in later years . Visit adherence worsened over time, with 6.0% having missed visits in the first six months on treatment in 2004 and 35.4% in 2013. Most patients had five to six scheduled visits, and 84% who missed visits missed only one visit.Values of potential predictor variables by the year of ART initiation are shown in p<0.2 and hazard ratios remained the same. When other predictors and interactions were added back into the model using imputed data, blood pressure and interactions between age and sex, sex and haemoglobin and sex and NNRTI had p<0.2. These model variations were considered in IECV.Fit diagnostic graphs and Cox-Snell residuals indicated the Weibull model fit the data best. The final predictors from stepwise selection of predictors in the non-imputed model included age, sex, missed visits during the first six months on treatment, TB history, NNRTI, CD4, MCV and haemoglobin, and interactions between NNRTI and CD4, haemoglobin and CD4, and sex and CD4. When this model was fit to imputed baseline data, all variables still had We tested 12 models. The selected model  had the 3 had a 73% increase in hazards of failure compared with individuals with CD4 counts of 100–199 cells/mm3 at ART initiation. Individuals who missed visits in the six months following ART initiation were at a significantly higher risk of failure compared with those who missed no visits , and individuals on NVP rather than EFV had increased hazards of treatment failure . MCV, haemoglobin and history of TB were weaker predictors of treatment failure  was lower than desired (60%), but the model had good calibration, with a five-year predictive risk equivalent to the actual failure at five years. Risk groups of patients were identified using quintiles of calculated risk of failure in the population, and failure estimates from the model by risk group matched the actual failure by risk group over time.The main weakness of the study is the low discrimination score for the predictive model. The C-statistic of 60% implies that the model correctly identifies a patient is at higher risk than another patient 60% of the time in independent data. Including clinic site could improve model discrimination but could not be done in a predictive model intended for external use. Although not tested outside of South Africa, this model may be applied to other populations with similar demographic and clinical profiles. Future work could identify clinic settings that share predictors of ART failure for developing setting-specific models. The low discrimination score also indicates that treatment failure is a complex event, likely having determinants based on individual behaviour and external circumstances, and therefore cannot be very precisely identified through a model of baseline clinic, lab and demographic variables. Missing data were also a weakness of the study. Multiple imputations were used so that patients with missing predictor variables could be included. Impact of missing or misclassified outcomes was explored in sensitivity analyses.The main strength of the model is its ability to provide insight into factors associated with the risk of treatment failure and their relative influence, and to identify risk groups of patients most likely to fail. Practically, the identification of high-risk groups for treatment failure has an important application in clinical settings, where high-risk patients could be monitored more closely and receive treatment adherence counselling or other interventions . The larOur treatment failure model was able to identify patients at risk of failure; estimate the proportion of patients failing treatment over time for those who remain in care; and emphasized the importance of CD4 count, age, sex and visit adherence in determining patients at risk of failure. Future work could expand the model to account for patients who are lost to care, since estimating outcomes for all patients regardless of whether or not they stay in care would be helpful for public health planning. In addition, further research into best practices for ART adherence interventions is an important next step in order to effectively improve outcomes for high-risk patients.


Introduction: For people living with HIV, the first antiretroviral treatment (ART) regimen offers the best chance for a good virological response. Early identification of those unlikely to respond to first-line ART could enable timely intervention and increase chances of a good initial treatment response. In this study we assess the extent to which the HIV RNA viral load (VL) at 1 and 3 months is predictive of first-line treatment outcome at 6 months.Methods: All previously ART-naive individuals starting ART at two London centres since 2000 with baseline (−180 to 3 days) VL >500 c/mL had a VL measurement between 6 and 12 months after starting ART, and at least one at month 1 (4–60 days) or month 3 (61–120 days) were included. Lack of treatment response was defined as (i) VL >200 copies/mL at 6 months or (ii) VL >200 copies/mL at 6 months or simultaneous switch in drugs from at least two different drug classes before 6 months. The association with VL measurements at 1 and 3 months post-ART; change from pre-ART in these values; and CD4 count measurements at 1 and 3 months were assessed using logistic regression models. The relative fit of the models was compared using the Akaike information criterion (AIC).Results: A total of 198 out of 3258 individuals (6%) experienced lack of treatment response at 6 months (definition i), increasing to 511 (16%) for definition (ii). Those with a 1-month (day 4–60 window) VL of <1000, 1000–9999, 10,000–99,999 and >100,000 copies/ml had a 4%, 8%, 23% and 24% chance, respectively, of subsequently experiencing treatment non-response at 6 months (definition (i)). When considering the 3-month (day 61–120 window) VL, the chances of subsequently experiencing treatment non-response were, respectively, 3%, 25%, 67% and 75%. Results were similar for definition (ii).Conclusions: Whilst 3-month VL provides good discrimination between low and high risk of treatment failure, 1-month VL does not. Presence of a VL >10,000 copies/ml after 3 months of ART is a cutoff above which individuals are at a sufficiently higher risk of non-response that they may be considered for intervention. For people living with HIV, the first antiretroviral therapy (ART) regimen offers the best chance for a good virological response, which, if achieved, then minimizes the chance of developing resistance ,2. AbiliSeveral studies conducted to evaluate predictors of virological response to ART in treatment-naive patients have found an association between higher pre-ART HIV RNA viral load (VL) and increased risk of treatment failure by 6–12 months –9. FurthThis study assesses the ability of the very early VL response to first ART at 1 and 3 months to predict subsequent initial treatment outcome at 6 months in a routine clinical setting among people starting ART from 2000 to 2014.Individuals included in this study were HIV-positive attendees aged ≥18 years at two outpatient clinics in London: the Ian Charleson Day Centre at the Royal Free Hospital and the Mortimer Market Centre. Information was collected from medical notes and electronic records and included demographics, ART treatment history and all VL and CD4 count measurements.Those included were previously ART-naive and starting an ART regimen consisting of three or more antiretrovirals, including exactly two nucleoside reverse transcriptase inhibitors (NRTIs) and exactly one of a ritonavir-boosted protease inhibitor (PI), non-NRTI (NNRTI), raltegravir or maraviroc between 1 January 2000 and 1 October 2015. In addition, individuals were required to have a baseline VL >500 copies/mL  measured in a window of −180 to +3 days from the start date of the first regimen (“baseline”); a 6 month VL, defined as the first VL between 6 and 12 months after starting ART, and at least one VL measurement at 1 or 3 months. Windows from day 4 to day 60 and from day 61 to day 120 were used, respectively, to define 1 month and 3 month measures. If more than one measurement was recorded in these windows, that closest to 1 and 3 months, respectively, was used.treatment non-response was defined in two ways: (i) 6 month VL >200 copies/mL or (ii) either 6 month VL >200 copies/mL or simultaneous switch/stop of antiretrovirals of at least two drug classes by 6 months. A cutoff of 200 copies/ml was used as low-level blips likely do not constitute treatment failure. The inclusion of treatment switch/stop was intended to capture situations where treatment was changed due to perceived virological failure prior to 6 months. Switch of drugs from two or more classes was required to exclude switches made solely for toxicity reasons. Only switches and stops made 28 days to 6 months after starting ART were included.The outcome of 10 scale. Multivariable analyses were adjusted for age (continuous), ethnicity , gender/likely HIV acquisition route  and treatment type . To compare the predictive ability (goodness-of-fit) between the different measures, the Akaike Information Criterion (AIC) for the models were calculated , median CD4 cell count was 222 cells/mmA total of 198 individuals (6%) had a VL >200 copies/ml after 6 months of ART, and so experienced a lack of treatment response using definition (i). An additional 313 individuals stopped or switched antiretroviral (ARV) drugs from at least two drug classes (median [IQR] time to stop/switch: 105 [57–149] days), leading to 16% (511) experiencing a lack of treatment response using definition (ii). A total of 39 individuals experienced both VL >200 copies/ml and made an eligible ARV change. Of the individuals with lack of treatment response according to definitions (i) and (ii), 84 out of 198 (42%) and 270 out of 511 (53%), respectively, had achieved VL <200 copies/mL at month1 and/or at month 3.Of those who achieved VL <200 copies/ml on their 1 month VL value, only 4% did not have a treatment response at 6 months using definition (i) ,Figure 1p < 0.001; chi-squared test). When considering definition (ii), these figures were 14%, 16%, 34% and 62%, respectively (p < 0.001). Similar trends were seen for the 3-month VL, with even greater differences between groups in the probability of non-response. The figures were 3%, 25%, 67%, 75% for definition (i) and 9%, 29%, 89%, 85% for definition (ii), respectively (p < 0.001). For both the 1- and 3-month time points, and for both endpoint definitions, the risk of treatment non-response substantially increased at a VL cutoff of 10,000 copies/ml, with a further increase above 100,000 copies/ml for definition (ii).compared to 8%, 23% and 24% among those with a 1 month VL of 1000–9999; 10,000–99,999 and ≥100,000 copies/ml, respectively  of treatment non-response by 6 months (definition (i)) compared to those who had VL <10,000 copies/ml, and 4.2 times the odds using definition (ii) , see Table. After 3 months of ART, individuals with a VL ≥10,000 copies/ml had almost 51.2 times the odds  under definition (i) and 60-fold increased odds using definition (ii)  to have treatment non-response at 6 months.To assess the ability to predict treatment response, the AIC was calculated based on logistic regression models in which each measure  was modelled as a continuous rather than a categorical variable .Table 1.p = 0.002); women  and those of black ethnicity  had higher odds of treatment failure at six months using definition (i). Increasing age , ethnicity others OR = 1.24, CI 0.62–2.57; p = 0.545 and those on an NNRTI-containing regimen  were not significantly different.The results indicate that for either definition of response, and for univariate or multivariate models, the 3 month VL has the best predictive ability of the measures considered. Conversely, CD4 count at 1 and 3 months did not predict non-response in multivariate models. In addition, men who likely acquired HIV heterosexually  compared to definition (i) suggests that clinicians are already successfully intervening in this group through treatment changes before the 6-month time point was reached. These early VL results are reported to treating clinicians, who may be interpreting them as an early measure of adherence and intervene accordingly. Nonetheless, the large effect sizes seen in this study suggest that further intervention could be possible.In previous studies, baseline VL has been shown to be associated with the probability of achieving VL <500 copies/ml . Early VIn our analysis, we only included those with a sufficient number of VL measurements. Therefore, we may have excluded infrequent clinic attenders or those lost to follow-up, for whom levels of treatment response may be poorer. We did not have data for all participants on the reasons for switching or stopping in our data set and so we attempted to capture stopping due to perceived treatment failure by using a definition that incorporated major changes to the ART regimen. Our sample included only a small number of people starting integrase inhibitors which are now recommended as part of first-line regimens , and so Very early VL measures taken 1 and 3 months after the start of ART could be a useful indicator of initial treatment non-response. We suggest that a value >10,000 copies/ml at 3 months identifies individuals at a high risk of non-response at 6 months and should prompt specific interventions, such as initiating adherence support strategies. This criterion could also be used to select a population to test candidate interventions, such as addition of an agent from another class of ART.


Introduction: Little is known about the impact of antiretroviral therapy (ART) guideline changes on the durability of second-line ART and continuity of care. This study examines predictors of early drug substitutions and treatment interruptions using a cohort analysis of HIV positive adults switched to second-line ART between January 2004 and September 2013 in Johannesburg, South Africa.Methods: The main outcomes were having a drug substitution or treatment interruption in the first 24 months on second-line ART. Kaplan Meiers analyses and Cox proportional hazards regression were used to identify predictors of drug substitutions and treatment interruptions.Results: Of 3028 patients on second-line ART, 353 (11.7%) had a drug substitution  and 260 (8.6%) had a treatment interruption . While treatment interruptions decreased from 32.5 per 100PY for the 2004 cohort to 2.3 per 100PY for the 2013 cohort, the rates of drug substitutions steadily increased, peaking at an incidence of 26.7 per 100PY for the 2009 cohort and then decreased to 4.2 per 100PY in the 2011 cohort. Compared to the 2004 to 2008 cohorts, the hazard of early drug substitutions was highest among patients switched to AZT + ddI + LPVr in 2009 to 2010  but remained low over time among patients switched to TDF + 3TC/FTC + LPVr or AZT/ABC + 3TC + LPVr. The main common predictor of both treatment interruption and drug substitution was drug toxicity.Conclusions: Our results show a rapid transition between 2004 and 2010 ART guidelines and concurrent improvements in continuity of care among second-line ART patients. Drug toxicity reporting and monitoring systems need improvements to inform timely regimen changes and ensure that patients remain in care. However, reasons for drug substitutions should be closely monitored to ensure that patients do not run out of treatment options in the future. With approximately 2.5 41.6%) of 6 million HIV-infected South Africans currently on antiretroviral therapy (ART) .6% of 6 . BetweenAlthough new drugs for HIV treatment are being developed, HIV treatment options within national programmes remain limited. Therefore the durability of second-line regimens is critical to the long-term success of ART and ultimately patient survival. In many low and middle income countries (LMIC) with no third-line regimens available, second-line ART is the last option for patients . In SoutThe South African ART guidelines were modified in 2010, 2013 and updated in 2015 to align with global recommendations –22. A maContinuity of care is closely associated with positive ART outcomes . UnfortuWe set out to examine patterns and predictors of early drug substitutions and treatment interruptions over the first two years on second-line ART for patients initiated on second-line ART between 2004 and 2013.This was an analysis of anonymized electronic medical records of HIV infected adults (≥18 years at ART initiation) switched to standard second-line ART (defined as a triple ART including a PI) after initiating a standard first-line regimen between January 2004 and September 2013 at clinics in Johannesburg, South Africa. We included patients from three non-governmental organization (NGO)-run clinics, four public community health centres (CHCs) and three HIV clinics embedded in public hospitals that receive HIV care and treatment technical support from Right to Care (RTC), a non-profit organization. CHCs are mainly nurse-run with the support of one medical doctor while hospital-based and NGO-run clinics often have more doctors available. The management of patients in both the public and NGO clinics follows national HIV treatment guidelines –22.Before April 2010, the primary second-line regimen in South Africa included two nucleotide reverse transcriptase inhibitors (NRTIs) (zidovudine (AZT) and ddI) and ritonavir-boosted lopinavir (LPVr) as the PI component. In 2010, ddI was replaced by new NRTIs (tenofovir (TDF) and abacavir (ABC)) alongside LPVr. In 2013, ritonavir-boosted atazanavir (ATVr) was also added as a PI option along with LPVr –21 Figu. LamivudUntil 2013, HIV positive women with high CD4 counts who became pregnant while stable on first-line ART, substituted efavirenz (EFV) with LPVr as part of first-line ART  and thenTM. Additional clinical and laboratory data were obtained from electronic records from the National Health Laboratory Services (NHLS). Data were fully anonymized for analyses. Ethics approval for the retrospective data review was obtained from the Human Research Ethics Committee of the University of Witwatersrand (M140201) as well as Boston University Institutional Review Board (H-29768). In accordance with Section 3 of the recommendations regarding the provisions for waiver or alteration of the informed consent requirements under the South African Department of Health and Human Services (HHS) Regulations at 45 CFR 46.116(d) and the Declaration of Helsinki, a waiver for individual patient consent was obtained.Clinical data from the ART clinics were captured by employees of RTC on site and stored on an electronic patient management system, TherapyEdge-HIVThe primary outcome was a drug substitution in the first two years (early) after initiating second-line ART that did not constitute a switch to a third-line regimen. Third-line was defined as any regimen including darunavir (DRV), etravirine (ETR) or raltegravir (RAL). We firstly hypothesized that rates of early drug substitutions would be lower among patients initiated on second-line under the 2010 and 2013 ART guidelines compared to the 2004 guidelines as better second-line regimens were made available. Participants were therefore categorized into annual cohorts based on the calendar year of switch to second-line ART (primary exposure). These were grouped into 2004 to 2008, 2009 to 2010 and 2011 to 2013 periods.Additionally, we hypothesized that changes in ART guidelines would have resulted in decreased treatment interruptions over time as alternative drugs became available. Treatment interruption was measured as gaps between the initial second-line regimen end date and new regimen start date. Participants were considered to have interrupted treatment if this gap was ≥7 days.We defined baseline as the time of initiating second-line ART. Variables collected at baseline included: (i) demographic variables; (ii) clinical and laboratory variables , CD4 counts, viral load and haemoglobin level); (iii) treatment variables ; (iv) measures of liver function (aspartate transaminase (AST)/alanine transaminase (ALT) ratio). These indicators were considered baseline if they were taken between 6 months before and 3 months after initiation of second-line ART.BMI was categorized as underweight (BMI < 18.5), normal (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30) and obese (BMI ≥ 30). Anaemia was defined as a haemoglobin (Hb) value below 13.0 g/dl in men and below 11.5 g/dl in women. VL failure during the observation period was defined as having two consecutive viral load measurements >1000 copies/ml, ≥3 months apart and 3 months after the date of second-line regimen initiation. Possible ADR during follow-up were obtained from clinical visit data . ALT andPerson time accrued from the date of second-line ART initiation until the outcome of interest, completion of the two years on second-line ART, the last date seen at the clinic during the first two year  or 30 August 2015 (administrative censoring). Loss to follow-up was defined as being ≥3 months late for a scheduled visit.p value <0.1 in crude analyses were entered in the multivariate model. Schoenfeld residuals were used to test the assumption of proportional hazards. Interaction terms with time varying covariates were created for variables that violated the proportional hazards assumption. Variables were excluded from the model when the inclusion of the interaction term did not resolve the proportional hazards assumption violation, except for the initial second-line regimen, in which case the model was stratified. Missing data was accounted for by including a ‘not measured/missing’ category where necessary.Data analysis was conducted using STATA version 14 . Continuous variables were described using medians and interquartile ranges. Categorical variables were described using percentages. Kaplan Meier analyses were conducted for each outcome of interest. Predictors of drug substitutions/treatment interruptions were modelled using Cox Proportional Hazards model. Variables with a n = 353) of patients had an early drug substitution at a median time of 10.6 months (IQR: 4.6–17.5). Overall 30% of patients who started on AZT + ddI + LPVr had a drug substitution and 96.5% (167/173) of substitutions involved swapping out ddI. Only 6.5% of patients initiated on AZT/ABC + 3TC + LPVr had a substitution and 61.1% (44/72) of cases involved swapping out AZT. Among patient initiated on TDF + 3TC/FTC + LPVr for second-line, 8.4% had a substitution and 46.7% (50/107) of cases involved swapping out TDF and 30 (28.0%) involved swapping out LPVr.Substitutions of ABC, AZT or TDF were made in the first 6 months after switching to second-line ART , ddI and LPVr substitutions were made over six months after switch . Only 88 (24.9%) of patients with drug substitutions had a possible ADR.Overall, the risk of drug substitution was higher after 2009 as compared to the 2004–2008 cohorts, the hazard ratio for drug substitution was 3.6 (95% CI: 2.6–4.9) for the 2009–2010 cohorts and 2.6 (95% CI: 1.7–4.1) for the 2011–2013 cohorts. This is only true however for patients initiated on AZT + ddI + LPVr for second-line in 2009–2010  and 2011–2013  when ddI was being phased out. Among patients initiated AZT/ABC + 3TC + LPVr or TDF + 3TC/FTC + LPVr for second-line, rates of drug substitutions remained low over time.Additional predictors of early drug substitutions were CD4 at switch to second-line ART, anaemia, reporting a possible ADR and being late for a scheduled visit during follow-up period. Patients with missing CD4 data around the time of initiating second-line ART were at higher risk of drug substitution compared to those with low CD4 values (<200 cell/µl), particularly those initiated on AZT/ABC + 3TC + LPVr . Patients who were anaemic at the time of switch were at higher risk of a drug substitution compared to those with normal haemoglobin levels, particularly those initiated on AZT/ABC + 3TC + LPVr .Patients who experienced an ADR during the observation period were more likely to have been switched following an ADR on first-line ART . Furthermore, experiencing a possible ADR during follow-up increased the risk of a drug substitution . However patients who were late for a scheduled visit had a lower risk of drug substitution compared to those who attended the clinics on time .The South African HIV treatment programme has evolved substantially since 2004. This is the first paper to examine in detail the impact of guideline changes on rates and predictors of early drug substitutions (in the first 24 months) and treatment interruptions after switching to second-line ART, over the first 11 years of South Africa’s national treatment programme. Among patients initiated on second-line between 2004 and 2013, 11.7% had at least one drug substituted in the first 24 months on second-line, at an overall rate of 8.6 per 100PY. Early drug substitution considerably increased in 2009 and early 2010 among patients initiated on ddI-based second-line regimen and then gradually decreased in for the later second-line cohorts. Treatment interruption on the other hand consistently decreased over time.The rate of early drug substitution for patients initiated on TDF + 3TC/FTC + LPVr is similar to the reported rate for patients on TDF based first-line regimens (6.3 per 100PY) ,26. DrugEarly drug substitutions were mainly driven by ddI substitutions centred around 2010, indicating a rapid phasing out of ddI and transition to newly available drugs as per the 2010 ART guidelines . The 201Drug substitutions were also associated with ADR experiences on second-line ART. In general ADR experiences increase the risk of treatment non-adherence and ART failure, and unresolved non-adherence on first-line ART is an important predictor of VL failure on second-line ,13,28,29The decrease in treatment interruptions over time highlights improvements in continuity of care among second-line ART patients after guideline changes in South Africa. The 2004 to 2008 rate of second-line ART interruptions is substantially higher than the reported rates for the general population on ART in the same period , suggestAs hypothesized, ADR experiences increased the risk of treatment interruptions. While improvements in ART monitoring in South Africa have been noted over the years, ADRs are still under-reported, thus limiting our ability to explain changes in treatment interruptions more accurately . The risThe interpretation of these results is limited to the context from which participants were drawn. The data for this analysis were drawn from a sample of public/NGO health facilities in Johannesburg and patients included may not be representative of patients across South Africa. Furthermore treatment interruption (as a proxy for continuity of care) may have been underestimated as only treatment breaks involving regimen changes was considered. The analysis does not account for treatment interruption within ART regimen. The lack of complete information on the clinical reasons for the drug substitutions or treatment interruptions further limit our ability to accurately examine drug toxicity related predictors of early drug substitutions among patients initiated on second-line regimen.Our results show a relatively rapid transition between 2004 and 2010 ART guidelines, highlighting the health system’s responsiveness to changes in HIV treatment policies and improved continuity of care among second-line ART patients. Drug toxicity reporting and monitoring systems, particularly among second-line ART patients, need improvements to inform timely regimen changes and ensure that patients remain in care. However reasons for drug substitutions should still be closely monitored to ensure that patients do not run out of treatment options in the future.


Stockouts of HIV commodities increase the risk of treatment interruption, antiretroviral resistance, treatment failure, morbidity and mortality. The study objective was to assess the magnitude and duration of stockouts of HIV medicines and diagnostic tests in public facilities in Kinshasa, Democratic Republic of the Congo. This was a cross-sectional survey involving visits to facilities and warehouses in April and May 2015. All zonal warehouses, all public facilities with more than 200 patients on antiretroviral treatment (ART) (high-burden facilities) and a purposive sample of facilities with 200 or fewer patients (low-burden facilities) in Kinshasa were selected. We focused on three adult ART formulations, cotrimoxazole tablets, and HIV diagnostic tests. Availability of items was determined by physical check, while stockout duration until the day of the survey visit was verified with stock cards. In case of ART stockouts, we asked the pharmacist in charge what the facility coping strategy was for patients needing those medicines. The study included 28 high-burden facilities and 64 low-burden facilities, together serving around 22000 ART patients. During the study period, a national shortage of the newly introduced first-line regimen Tenofovir-Lamivudine-Efavirenz resulted in stockouts of this regimen in 56% of high-burden and 43% of low-burden facilities, lasting a median of 36 (interquartile range 29–90) and 44 days (interquartile range 24–90) until the day of the survey visit, respectively. Each of the other investigated commodities were found out of stock in at least two low-burden and two high-burden facilities. In 30/41 (73%) of stockout cases, the commodity was absent at the facility but present at the upstream warehouse. In 30/57 (54%) of ART stockout cases, patients did not receive any medicines. In some cases, patients were switched to different ART formulations or regimens. Stockouts of HIV commodities were common in the visited facilities. Introduction of new ART regimens needs additional planning. Ending HIV will require resilient supply chains to ensure uninterrupted access to diagnostics and antiretroviral treatment (ART). Stockouts of testing kits and antiretroviral drugs (ARVs) may prevent countries from reaching the international 90-90-90 targets, i.e. for 90% of people living with HIV/AIDS (PLHIV) to know their HIV status, to put 90% of those diagnosed on ART and to keep the viral load suppressed in 90% of those on ART by 2020 ,2. StockMost countries, including those in Sub-Saharan Africa, aim for universal HIV treatment and provide access to cheap, one-pill-a-day regimens for the majority of the PLHIV . HoweverAs a response to rising reporting of global shortages, WHO has passed a resolution calling to assess the nature and magnitude of stockouts and shortages and to install early warning systems for prevention of local and national stockouts . Yet couIn the Democratic Republic of the Congo (DRC), country-wide information about stockouts of HIV commodities is not available. Indications of severe interruptions in ART and cotrimoxazole supply have however been reported by patient groups in Kasa-Vubu and North-Kivu ,18. In KThis study thus aimed to assess the magnitude and duration of stockouts of HIV commodities in public facility dispensaries and zonal warehouses in the province of Kinshasa, and to describe coping mechanisms to deal with stockouts at the level of the facilities.This was a cross-sectional survey including data collected through visits to facility pharmacies and warehouses in Kinshasa in April and May 2015.The DRC is the largest country in Sub-Saharan Africa, with a population of over 75 million, of which 40% live in urban areas . CountryIn the DRC, HIV commodities are almost exclusively funded and procured by international donor agencies such as the Global Fund for AIDS, Tuberculosis and Malaria (GFATM) and the United States President’s Emergency Plan for AIDS Relief (PEPFAR). Supply chains are highly fragmented, with multiple tiers and supply chains run by different actors . The DRCEach province has a provincial warehouse that is run as a semi-independent entity contracted by donors for storage and distribution of medicines to the different health zones. The province of Kinshasa has 35 health zones, each with a zonal warehouse serving health facilities. The maximum traveling time by car between any facility and the closest warehouse in Kinshasa is five hours, with some warehouses adjacent to facilities.In January 2015, the country had started a transition to a new first line regimen, leading to national supply disruptions at the time of the study. The study timing was not deliberately planned during this period but it created an opportunity to document the impact of the transition on ART availability in the facilities.The target population were ART-providing facilities in Kinshasa and zonal warehouses. For the study, facilities were sampled based on health zone and number of PLHIV under care. We did not include the military and the police health zones. From each of the 33 remaining health zones, we selected all the facilities with more than 200 patients on ART, the largest facility with 100 to 200 patients and the largest one with fewer than 100 patients on ART (if existent). This purposive sampling of low burden facilities was done to include facilities of different sizes and serving as many patients as possible, while considering feasibility and budget. We also targeted the 33 zonal warehouses.The variables included were the point prevalence of stockouts of a set of HIV commodities in the visited sites. A stockout was defined as no physical availability of the selected commodity in the facility pharmacy at the time of the survey visit. A complete first-line ART regimens consist of three active ingredients. Sometimes, two or more active ingredients are combined into a single tablet  to reduce the pill burden and improve adherence . We haveFor the 33 included health zones, the number of patients on ART was retrieved from the national database . For theStataCorp, College Station, TX, USA). Frequencies and percentages were used to describe categorical variables and medians with interquartile ranges for numerical variables.Data from the questionnaires were initially entered into Microsoft Excel 2015 by trained data clerks and then analysed with Stata software version 14 (The study fulfilled the exemption criteria set by the Ethics Review Board (ERB) of MSF, Geneva, Switzerland, for a-posteriori analyses of routinely collected data and thus did not require MSF ERB review. The study was also approved by the Ethics Advisory Group of the International Union Against Tuberculosis and Lung Disease, Paris, France. As this was a record review study, informed consent was not required. The study did not require ethical approval in country, but the protocol was approved by the provincial HIV programme of Kinshasa.We obtained information from 92 facilities serving 82% of the 26649 ART patients registered in Kinshasa, or 85% of the cohort registered outside police and military zones. We included 28 of the 35 high-burden health facilities in Kinshasa . These wThe number and duration until the survey visit of stockouts of HIV commodities is shown in CTX tablets were out of stock in 18% (5/28) of high-burden and 8% (5/62) of low-burden facilities. Out of 18500 patients registered on cotrimoxazole, 3200 (17%) were attending those facilities with a stockout. HIV test kits were not available in 5 (18%) out of 28 high-burden facilities and 18 (28%) of the 64 low-burden facilities.Out of 28 high-burden facilities, 13 (46%) had 1 item out of stock and 8 (29%) had 2 stockouts . Out of For 41  stockout events of AZT-3TC-NVP, TDF-3TC, CTX or HIV tests in health facilities, we could check the associated zonal warehouse. In 30 (73%) of these stockout events, a product was absent at the facility but present at the warehouse during the same period. The median time between facility and warehouse visits was 6 days (IQR: 5–20).Overall, in 30 out of 57 cases (54%) of ART stockouts, patients left the facility without any ART. In the case of TDF-3TC-EFV stockouts where ART was given (24/37), patients received another formulation , or a substitution regimen . In the remaining 7% (1/15) of high-burden and 55% (12/22) of low-burden facilities with TDF-3TC-EFV stockouts, no alternative ARV was given. In the case of AZT-3TC-NVP stockouts, the patients did not receive any ARV in all 10 facilities facing a stockout. In facilities with TDF-3TC stockouts, 2 out of 10 reported substituting the regimen with AZT-3TC-NVP, while 8 reported giving no ARVs.Out of 92 facilities visited, 16% commonly provided one ARV (n = 15), 38% two ARVs (n = 35) and 46% all three surveyed ARVs (n = 42). Those facilities providing more ARVs where at higher risk of stockouts, but those with three ARVs were better placed to provide a substitution regimen. Out of those facilities commonly stocking only one ARV, 20% had a stockout (3/15) on the day of the survey visit, of which 1 (33%) managed to substitute the missing ARV. Among those facilities commonly providing two ARVs, 48% (17/35) had a stockout, of which 29% (5/17) provided a substitute. Among those commonly stocking three ARVs, 67% (28/42) had at least one ARV missing, out of which 68% (19/28) provided a substitution regimen.The study indicates that stockouts of different HIV commodities are frequent in the included public health facilities in Kinshasa, with stockouts often lasting several days to weeks and affecting facilities serving varying numbers of patients. This is a problem for individual and public health because it puts more people at risk of HIV transmission and viral resistance and it increases morbidity and mortality, particularly in patients with low immunity ,7.When stockouts occurred, the staff at the facilities substituted the missing ARV with other ARV formulations or regimens, referred patients to other centres, or asked them to return later. Similar coping strategies have been described in response to ART stockouts in Tanzania, leading to increased cost for patients, higher risk of treatment interruption and emergence of resistant strains . TDF stoSide effects due to TDF-3TC-EFV are less frequent and the pill burden is lighter as compared to AZT-3TC-NVP . SubstitThis study has several limitations. First, the stockouts were measured on the day of the survey visit, which produces a point estimate and does not reflect an average stockout rate. In case of a stockout, we used stock cards to estimate stockout duration, but this duration could only be measured until the visit date, and stockouts might have lasted longer. Also, when commodities were available, their expiry date was not verified as part of the study. This means that even when available, some items might have not been usable. A second limitation is the fact that the included low-burden facilities were not randomly sampled from the facilities in the province of Kinshasa, leading to selection bias. Thus, even if approximately 82% of the patients on ART in Kinshasa received treatment in the included facilities, it cannot be assumed that this survey is representative for Kinshasa. This is illustrated by the median [IQR] patient burden, which in high burden facilities is 429 [287–670] in the population and 450 [317–686] in the selection. However, in low-burden facilities the median patient burden is 4 –37 in thThe survey results suggest that two types of stockouts occurred in the facilities during the analysis: stockouts of an item for which there were national shortages and stockouts of items available in country. Due to the national shortage of TDF-3TC-EFV, it is not possible to draw conclusions on availability of this regimen under routine conditions. A similar cross-sectional study in Kinshasa from 2016 showed that TDF-3TC-EFV was available in a larger proportion of facilities after the national shortages had been corrected . Only 2%Implementation of guidelines changes, like the introduction of TDF-3TC-EFV are likely to happen every few years, as evidence for better treatment becomes available. Supply chain problems at scale-up and decentralisation of ART have been documented before . In SoutThe second type of stockouts observed in 2015 were of items that were available at national level and even frequently in a nearby warehouse, but absent in the facility. While the national stockout during this period led to increased facility stockouts of TDF-3TC-EFV and the substituting regimens, the high proportions of stockouts of test kits and CTX indicate a structural, systematic problem in supply chain. These findings show that medicines often do not reach patients due to problems in the final part of the supply chain, despite the short distances between facilities and warehouses in Kinshasa. In the 2016 analysis, most items were stocked out less often than in 2015. However, not one of the investigated items was available in all high-or low-burden facilities, indicating ongoing supply challenges due to chronic and structural supply chain problems.The lack of data from the last level in the supply chain has contributed to a neglect of attention to the last mile and denial of stockout existence in many countries. In South Africa stockouts are reported by citizens through a free telephone number and traced up the supply chain, with all cases published on a public website , 33. ThiActions are also necessary to ensure ‘last mile’ delivery. Simplifying the supply chain by reducing the tiers, installing informed push systems or direct delivery to the last mile have shown benefit in other settings –37. InfoAs pointed out by Bogaert et al., the lack of publicly available data on stockouts and problems surrounding definitions of stockouts and shortages have led to limited global quantification of stockouts and the identification of their causes. In that qualitative study, European stakeholders identified manufacturing, economic, supply and distribution problems, as the main causes of stockouts . The WHAAt the time of this survey, no internationally recognised definition of drug stockouts existed and we based ourselves on the WHO definition for stockouts of ART as early warning indicators for drug resistance . The defThe results of this study have been presented at national multi-stakeholder meetings. The data and additional analyses by the ministry of health and its partners have led to proposals for corrective actions. In the second half of 2015, the two main donors (GFATM and PEPFAR) reallocated the different health zones of Kinshasa for support by only one donor at a time, but optimal ongoing coordination will be necessary to avoid duplication and gaps. Due to the limitation of this cross-sectional design, repeated analysis and regular monitoring are needed to describe trends for the stockouts unrelated to the national shortage and to monitor management of future regimen introductions. Further research is also needed to assess the situation in more remote parts of the country.This study provides quantitative data on stockouts of HIV commodities occurring in the field, where the last mile is neglected and where transition from one to another ARV regimen puts an additional strain on supply systems. In the DRC, like in other countries in West-and Central Africa, supply chains need fixing to catch up with global targets to end HIV.S1 Dataset(DTA)Click here for additional data file.S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file.


Combination antiretroviral therapy (cARTs) regiments are known to prolong the recipients’ life even though they are risk factors for diabetes mellitus-related comorbidities (DRCs). We sought to: (i) examine cART relationship with DRCs among patients attending HIV clinics in Gaborone, Botswana (which cART regimens are associated with shorter/longer time to the event), (ii) characterize patients’ underlying biomedical and demographic risk factors of DRC and identify the most important, (iii) investigate survival of patients on different cART regimens in the presence of these risk factors.Data from two major HIV clinics in Botswana were reviewed. Relationships between different cART regimens and DRCs were investigated among 531 recipients. Recipients’ DRC risk factors were identified. Cox regression model was run. Unadjusted and adjusted hazard ratios were computed, and hazard and survival functions for different cART regimens were plotted.3 at cART initiation were more likely to develop DRCs earlier than those who had CD4 count > 200 cells/mm3. Overweight patients at cART initiation had a higher risk of developing DRCs earlier than those who had normal body mass index. Males had a lower risk of developing DRCs earlier than females.Major findings were: patients on second- and third-line cART were less likely to develop DRCs earlier than those on first-line cART. Patients with CD4 count ≤ 200 cells/mmThe risk of new onset of DRC among cART recipients is a function of the type of cART regimen, duration of exposure and patients’ underlying biomedical and demographic DRC risk factors. The study has provided a survival model highlighting DRCs’ significant prognostic factors to guide clinical care, policy and management of recipients of cARTs. Further studies in the same direction will likely improve the survival to the development of DRC of every cART recipient in this community. Human Immunodeficiency Virus (HIV) patients are now living longer than before , 2. ThisAssociation between cART and DRCs has been long suspected , 6, 7. S3 have the potential to alter outcomes among patients if not well controlled  of participants was 41.4 ± 8.9 years. The youngest was 19 years old while the oldest aged 82.0 years. The mean (± SEM) weight of patients at cART initiation was 60.6 ± 11.8 kg with the lowest record of 17.5 kg and 101.0 kg as the highest. After cART initiation the mean (± SEM) weight documented was 67.9 ± 14.50 kg, with the minimum of 32.5 kg and 117.7 kg as the maximum. The mean CD4 count (± SEM) at cART initiation was 139.5 ± 5.11 cells/mmResults presented in Table p = 0.9]. When patients on second-line cART were aggregated with those on third-line (cART line2/3), recipients showed 51% less risk of developing DRCs earlier than patients who were not on cART line2/3 . Patients on second-line cART had a 52% less risk of developing DRCs earlier than patients who were not on the second-line cART . Those on third-line cART had 5% less risk of developing a DRC earlier than patients not on the third-line cART but the relationship was not statistically significant  for every one year increase in recipients age. Of all the characteristics investigated, seven showed significant crude associations with DRCs ]. Participants who reported adherence to cART had a 3.1 times higher risk of developing DRCs earlier than those who did not adhere . Overweight patients at initiation of cART, had a 63% higher risk of developing DRCs earlier than recipients who had normal BMI at cART initiation . Males had a 51% lower hazard of the outcome than females . Age as a continuous variable did not enter the multivariate model as it did not achieve a p < 0.05.HIV patients on second- and third-line cART (cART line2/3) were 47% less likely to develop DRCs earlier than those on first-line cART . Recipients of cART who had a CD4–1 count equal to or less than 200 cells/mm. However, the most significant risk was documented among recipients of the first-line cART regimen while the least risk of new DRC cases per year of cumulative exposure to cART was recorded among recipients of the second-line cART regimen .The log rank (Mantel Cox) test confirmed that recipients of second-, third-line cART had significantly longer survival to DRC development than recipients of first-line cART (XFindings from this study bring new insights to the fight against HIV and related comorbidities. The risk of new DRC onset per year of cumulative exposure to cART was higher among recipients of first-line cART than in recipients of cART second-line and cART third-line regimens. The longest survival/time duration to the development of DRC per year of cumulative exposure to cART was documented among recipients of second- and third-line cART regimens. In other words recipients of the second-, and third-line cART were less likely to develop DRCs earlier than recipients of the first-line cART. This lends support to the claim that the survival of cART recipients to DRC development is not solely a function of the duration that patients are subjected to these drugs but also a function of the specific regimen they are exposed to , 20 and 3 were identified in this study as at more risk of developing DRCs earlier than those without and should have been put directly on second- or third-line regimen rather than starting with the first-line treatment. Recipients aged 35 years or older also need particular attention compared to those aged less than 35 years before being assigned to a specific cART regimen.In short, important findings in this study were that recipients of the second-, third-line cART regimen were less likely to develop DRCs earlier than first-line cART regimen recipients. This is good news that may indicate that different cART regimens are differently associated with DRCs and different groups of recipients. Thus, depending on circumstances, the current second- and third-line regimens may be considered for use as first-line regimen while taking into account factors such as recipients’ pre-existing DRC risk factors, drug availability, cost-effectiveness, etc. For instance, patients with characteristics such as overweight, female gender or CD4–1 equal or less than 200 cells/mmHowever, the challenge lies in the cost difference between the first-line, the second- and third-line regimens and possible adverse effects of the third-line regimen. While WHO states that treatment programs using Tenofovir or AZT are promising, they may not be the ultimate solution to alleviate the situation since both drugs are known to be expensive  and yet 3 should be selectively assigned to treatment regimens for possible improvement of their survival.As with any other study, this study had some limitations. It was a retrospective review of data and may be missing some important DRC risk factors like physical activity, cigarette smoking, alcohol consumption and family history of DRCs. Prospective studies are needed to address this particular issue. Even so, the study has provided useful evidence to inform policy and decision making on alternative approaches for the management and care of HIV patients. The study has also indicated that patients with underlying DRC risk factors such as overweight, female gender, aged 35 years or older or those with CD4 ≤ 200 cells/mmThe study has shown that the risk of new DRC onset among cART recipients is not only a function of the type of cART regimen or the duration of exposure to these drugs but also a function of patients’ underlying biomedical and demographic DRC risk factors. The study has also presented a survival model highlighting DRCs’ significant prognostic factors to guide clinical care, policy and management of recipients of cARTs. Further studies in the same direction will likely improve the survival to the development of DRC of every cART recipient in this community.