Human Immunodeficiency Virus (HIV) is one of the main causes of morbidity and mortality; because of this it continues to be a major global public health concern. It has believed to kill more than 34 million lives so far. Sub Saharan Africa constitutes about 70% of people living with HIV among the 37 million on the globe. This region, accounted for more than two third of the global new HIV infections and about 15 million (40%) were receiving antiretroviral therapy (ART) at the end of 2014 throught the world. ART has fundamentally changed the treatment of HIV and transformed this infection from a disease of high mortality to chronic and medically managed disease. The issues of drug induced toxicities & complexity of current highly active antiretroviral therapy (HAART) regimens has remained of great concern. The aim of this study was to determine factors leading to antiretroviral regimen changes among HIV/AIDS Patients in the study area.A facility based retrospective cross-sectional study was conducted from April 28, 2017 to May 30, 2017 in the ART clinics of east and west Wollega zone health institutions using a pre-tested data collecting form and chart review. The sample included the 243 patients whose medication had been switched.Majority 145 (59.67%) of the patients had been on ART for > 10 years duration. More than half 126(51.9%) of the patients had received tuberculosis (TB) treatment and almost three out of five patients (57.2%) had received isoniazid & cotrimoxazole prophylaxis. The most common reason for regimen change was peripheral neuropathy 146(60.1%) and the most common medication for this reason was stavudine, lamivudine and neverapine based 108(44.44%).The number of patients who changed ARV drug in our resource constrained setting present a challenge to the restricted treatment choices that we currently own. Less toxic and better-tolerated HIV treatment options should be available and used more frequently. Human immunodeficiency virus (HIV) annihilates and compromises the function of immune cells. Immunity of infected individuals gradually depletes and susceptibility to a wide range of infections and diseases would be boosted. Acquired immunodeficiency syndrome (AIDS) is the most advanced stage of HIV infection, which can take from 2 to 15 years to develop depending on the individual and it can be explained by the progression of opportunistic infections, or other intense clinical manifestations and certain cancers [HIV is one of the main causes of morbidity and mortality; because of this it continues to be a major global public health concern. It has believed to kill more than 34 million lives so far. Sub Saharan Africa constitutes about 70% of people living with HIV among the thirty seven million on the globe. This region, accounted for more than two third of the global new HIV infections in 2014 with only 12% of the global population. Globally people receiving ART were about fifteen million (40%) among those living with HIV of which about fourteen million were in low- and middle –income countries and nearly one million were children [Ethiopia is among the countries most affected by HIV/AIDS with prevalence of 1.9% for women and 1.0% for men in 2011  and it iHighly active antiretroviral therapy (HAART) has fundamentally changed the treatment of HIV and changed this infection from a disease of high mortality to chronic and medically managed disease which is a radical change in controlling the hardship of HIV/AIDS. However drug resistance and side effects were the great concern in these advancements . RevolutThe goal of ART is to attain maximal and durable suppression of the viral replication. Viral suppression enables recovery of the immune response and thereby reduces risk of opportunistic infections (OIs) and death .3 irrespective of WHO clinical stage and active tuberculosis (TB) co-infection with HIV irrespective of CD4 cell count according to standard treatment guideline of Ethiopia [The decision to initiate ART for adults and adolescents depend on: WHO stage 3 and 4 disease irrespective of CD4 cell count, CD4 count ≤500cells/mmEthiopia .Triple combination therapy has been in use for more than two decades globally. Currently, the preferred first regimen triple therapy in Ethiopia consists of, two Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and one Protease Inhibitor (PI) or a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) or a triple therapy of three NRTIs. Based on the guideline, common ART regimens in the country are; Tenofovir (TDF)/ Emtricitabine (FTC)/ Efavirenz (EFV) or Nevirapine (NVP); alternatives are TDF/ Lamivudine (3TC) /EFV or NVP, Zidovudine (ZDV)/3TC/EFV or NVP. Other options are Abacavir (ABC)/3TC/NVP, ABC/3TC/EFV and ABC/3TC/ZDV. The second line regimen consists of ZDV ±3TC + Lopinavir/ritonavir (LPV/r) (or Atazanavir/ritonavir (ATV/r)), ZDV + ABC + LPV/r (or ATV/r), TDF/3TC ± ZDV + LPV/r (or ATV/r), ABC/ Didanosine (ddI) /LPV/r (or ATV/r), EFV or NVP / LPV/r (or ATV/r) , 9.Changes of multiple medications in HAART regimens were commonly required simultaneously. These changes may be due to co morbidity with other chronic diseases, a desire for pregnancy, poor adherence, stock out of drugs, treatment failure, long term toxicity or acute toxicity. The approaches to change ART regimens depend largely on amount of previous ART experience, available treatment options and reason for change. For example effective treatment can be accomplished by substituting another agent for the drug which has unpleasant effect in the regimen when it develops to certain drugs in the regimen , 10.The issues of drug toxicities and complexity of current HAART regimens has remained of great concern despite ARTs being of much help to the health of HIV/AIDS patients. Suboptimal therapy, discontinuation, and treatment failure can be resulted from treatment toxicities and adherence problems . The conKnowledge of the determinants of ART change may help to minimize the risk factors. These benefits in decreasing the rate of regimen change, treatment failure, drug resistance, and improve the quality of life of the patient. Antiretroviral treatment change should be done when necessary to spare the future treatment options. The approach to patients who need to switch will differ depending on several issues, including ART experience and available options. Regimen substitution requires adjustment in learning the new medication about the treatment dosing, time of intake and deal with many individual based inconveniences, which might be challenging and reason for non-adherence , 13.Data on modification of HAART and factors associated with ARV drug regimen change are limited among HIV/AIDS patients in Ethiopia. Most of the surveys used were on small sample of patients who were on ART for less than three years. As a result it is important to understand common reasons of ARV drug switch in patients on long period exposure to ART.Therefore, this study attempts to investigate the major determinants of HAART regimen change among HIV/AIDS patients in east and west Wollega zone health institutions by using cross-sectional study.✓ To assess determinants of antiretroviral regimen change among HIV/AIDS patients in east and west Wollega zone health institutions, Oromia region, west Ethiopia.✓ To assess determinants of antiretroviral regimen change among HIV/AIDS positive patients.✓ To identify the pattern of initial ART regimens and the subsequent changes.✓ To assess the relationship between patient characteristics and reasons for initial ART change.The study was conducted in the ART clinics of east and west Wollega zone health institutions, Oromia region, west Ethiopia; Nekemte town which is the capital of east Wollega is located 328 km where as Gimbi town which is the capital of west Wollega is 438 Km western to Addis Ababa .The area is well known by its coffee production. The economy of the people is based on subsistence farming and livestock rearing. The climatic condition of the area is ‘woinadega’ (semi-desert) and it is found at 2080 m above sea level.A facility based retrospective cross-sectional study was conducted by reviewing patient information sheets and physician diagnostic cards to assess reasons for HAART regimen change. The study was conducted from April 28, 2017 to May 30, 2017.All HIV/AIDS positive patients who were greater than 18 years and on HAART in east and west Wollega zone health institutions ART Clinic from April 28, 2007 to April 28, 2017 were the source population. All HIV/AIDS positive patients greater than 18 years who had undergone HAART regimen change in east and west Wollega zone health institutions ART Clinic in between April 28, 2007 to April 28, 2017 were the study population.✓ Patients on follow up in the ART clinic who had undergone HAART regimen change until the study period.✓ Patients on follow up in the ART clinic who were on second line regimen when the study was undergone.✓ HIV/AIDS patients who were greater than18 years.✓ Patients receiving HAART regimen for at least 6 months at the beginning of the study periodInclusion criteria:✓ Patient information cards with incomplete information .✓ Patients with less than 6 months on HAART regimen.✓ Patients who didn’t switch HAART regimen.✓ Under eighteen year old HIV/AIDS patients.✓ Deceased patients✓ Transfer out patientsExclusion criteria:A total of 243 patients who had undergone HAART regimen change in the ART clinics of east and west Wollega zone health institutions from April 28, 2007 to April 28, 2017 were included in the study while patients below 18 years were excluded from the study. Patient information cards that showed a change in the initial treatment regimen were assessed and analyzed, to identify the common reasons that resulted in a change from the initial treatment regimen.Independent variables✓ Socio-demographic characteristics: age at initiation, sex, marital status, educational status.✓ Disease related variables: baseline WHO stage, base line CD4, and baseline weight.✓ ART related variables: types of initial regimenDependent variables✓ Reasons for changeData abstraction form was developed based on the objectives of the study. It contained socio-demographic, clinical information and ART information such as, CD4 count, WHO stage, initial regimen, date on which treatment was started, date of ARV drug switch, duration of initial ARV therapy before first switch, regimen switched to, and causes for regimen change. The types of toxicity and treatment failure reasons were included. If there was ARV drug switch for the second and third time it was recorded in a similar manner. For data collection four 10th grade completed students were recruited. One pharmacist and one druggist from each health institutions were also recruited as supervisors.Data collectors were recruited and trained methods of data collection prior to the start of actual data collection.Training was provided for supervisors and data collectors and they were standardized. Data abstraction form was pre-tested on randomly selected patient information cards to identify any drawbacks in Shambu hospital which is found in Horro Gudru Wollega zone before the actual survey and improvements were made. The principal investigator supervised the data collection. Every questionnaire was checked for completeness and logical consistency.The data were coded and entered in to a computer using statistical Package for the Social Sciences (SPSS) software for windows version 20 and the analysis was performed after the data were cleaned, edited and processed. Distribution of Patients such as percentages and their number by socio demographic characteristics and other relevant variables in the study were described using descriptive analysis.An official letter was written by department of pharmacy, college of public health and medical sciences, Wollega University to zonal and woreda health offices of east and west Wollega zone Administration to get permission. After permission to conduct the study was obtained, data has been collected in one of refilling rooms at ART Clinic by safe keeping of records.Only numerical identifications were used as a reference, confidentiality and anonymity of subject was maintained by not recording and identifying details, such as name or any other personal details. No disclosure of any name of the patients, the healthcare provider or drug product was made in relation to the finding.ABC based regimen: regimen containing abacavir as one of the NRTI backbones and may have different NNRI or PI bases.Antiretroviral drug switch/change: it is the change of one or two ARV drugs from the initial drug regimens.AZT based regimen: regimen containing zidovudine as one of the NRTI backbones and may have different NNRI or PI bases.Co morbidity: is defined as the occurrence of one or more additional disorders which are on drug therapy with HIV/AIDS simultaneously .d4T based regimen: regimen containing Stavudine as one of the NRTI backbones and may have different NNRI or PI bases.TDF based regimen: regimen containing Tenofovir as one of the NRTI backbones and may have different NNRI or PI bases.Toxicity: is defined as the occurrence of adverse events such as diarrhea, nausea, vomiting, anemia, rash, fatigue, peripheral neuropathy, lipodystrophy, metabolic disturbances, CNS abnormalities or any other unwanted effect related to HAART.Transfer out: Patients who changed their follow up to other health institution.The mean age of patients was 43.68(SD ± 8.2) years. Majority of the patients 174(71.6%) were in the age range of 35–49 years and more than half 127(52.3%) of the patients were females. About 154(63.4%) of the patients were married. In this study only 77(31.7%) of the patients received greater than secondary school education. Regarding the family size 96(39.5%) of the patients had < 5 family size whereas 61(25.1%) had > 10 family size. Regarding place of residence 209(86%) were urban dwellers where as 34(14%) were rural dwellers as shown in (Table During initiation of ART 180(74.1%) of the patients were on WHO clinical stage III; whereas WHO stage after the ART switch was stage I for 237(97.53%) of patients. Similarly more than two third 180(74.1%) of patients had baseline CD4 count less than 200 cells/μL on initiation but most 190(78.19%) of patients had > 350 cells/μL after ART switch. In addition, the weight of the majority 164(67.5%) of patients during initiation of ART was between 45 and 60 kg (Table Majority of the patients 15965.4%) started their initial ART on D4t-3TC-NVP regimens, followed by D4t-3TC-EFV 55 (22.6%). Only 12% of patients started initial ART regimen on AZT based regimen (Table % startedThe HAART regimen of majority of the patients 168(69.14%) was changed to TDF based regimen. Whereas about 69(28.4%) of the patients initial HAART regimen was changed to AZT based regimen and only 62.5%) patients initial HAART regimen was changed to ABC based regimen  followed by hepatotoxicity, d4t faith out, CNS toxicity, Anemia, Rash etc. Table .Table 6CThe present retrospective cross sectional study of HIV/AIDS patients who changed their HAART regimen in east and west Wollega zone health institutions described the pattern of ART regimen and the common reasons for ARV drug switch. Such studies would be helpful in understanding the complexity of ART use of patients in health institutions which might have different co morbidities.Majority of the study population 145 (59.67%) had been on ART for > 10 years. This finding indicated longer duration as compared to other studies as all patients stayed on ART for less than 3 years in Bedelle  and in AThe main reason for initial ARV drug switch in the present study was toxicity which was known as peripheral neuropathy and it accounted for more than 60% of HAART regimen change. This finding was in agreement with the study conducted in some parts of Ethiopia . The othChange of the entire regimen from first-line to second-line is required in case of treatment failure. In order to increase likelihood of treatment success and minimize the risk of cross-resistance the new second-line regimen should involve drugs that keep activity against the patient’s virus strain and should preferably include at least three new drugs, one or more from a new class . The preThe study also found that there was high prevalence of TB as almost three out of five patients (57%) had received isoniazid & cotrimoxazole prophylaxis and more than half (52%) of the patients had been treated for TB , 19. NVPThe number of patients who changed ARV drug in our resource constrained setting present a challenge to the restricted treatment choices that we currently own. The main reasons for ART switch were toxicity among which Peripheral neuropathy and hepatotocity were the leading toxicity for ART switch. Less toxic and better-tolerated HIV treatment options should be available and used more frequently in east and west Wollega zone health institutions. Patient should be evaluated regularly after a treatment change to assess for potential concerns with the new regimen, medication tolerance and to assess the effectiveness. Information is needed on patterns of resistance across the population to recommend future therapy options. Therefore national and health institution based surveillance of antiretroviral drug resistance should be conducted. It helps to know the resistance pattern and select the locally effective treatments. National level study on reasons for regimen change should be done to help drug suppliers and policy makers to improve and solve the problem. The reasons of ARV drug switch observed in this cross sectional study should be investigated further in longitudinal multicenter studies of ART utilization.


The effect of peer support on virologic and immunologic treatment outcomes among HIVinfected patients receiving antiretroviral therapy (ART) was assessed in a cluster randomized controlled trial in Vietnam.Seventy-one clusters (communes) were randomized in intervention or control, and a total of 640 patients initiating ART were enrolled. The intervention group received peer support with weekly home-visits. Both groups received first-line ART regimens according to the National Treatment Guidelines. Viral load (VL) (ExaVir™ Load) and CD4 counts were analyzed every 6 months. The primary endpoint was virologic failure (VL >1000 copies/ml). Patients were followed up for 24 months. Intention-to-treat analysis was used. Cluster longitudinal and survival analyses were used to study time to virologic failure and CD4 trends.p < 0.01]; baseline VL ≥100,000 copies/ml  and incomplete adherence (self-reported missing more than one dose during 24 months) . Risk factors associated with slower increase of CD4 counts were: baseline VL ≥100,000 copies/ml  and baseline CD4 count <100 cells/μl . Having an HIV-infected family member was also significantly associated with gain in CD4 counts .Of 640 patients, 71% were males, mean age 32 years, 83% started with stavudine/lamivudine/nevirapine regimen. After a mean of 20.8 months, 78% completed the study, and the median CD4 increase was 286 cells/μl. Cumulative virologic failure risk was 7.2%. There was no significant difference between intervention and control groups in risk for and time to virologic failure and in CD4 trends. Risk factors for virologic failure were ART-non-naïve status [aHR 6.9;(95% CI 3.2–14.6); There was a low virologic failure risk during the first 2 years of ART follow-up in a rural low-income setting in Vietnam. Peer support did not show any impact on virologic and immunologic outcomes after 2 years of follow up.NCT01433601. Globally, the number of HIV-infected people receiving antiretroviral therapy (ART) was about 14.9 million by end of 2014, most of them living in low- and middle-income countries . To ensuIn sub-Saharan Africa, peer support and home-based care have become part of the HIV comprehensive care and treatment package –11, in wIn Vietnam, the ART programs have been rapidly scaling up with the support from PEPFAR and Global Fund to fight AIDS, Tuberculosis and Malaria (GFATM). By the end of 2010, more than 82,700 people had access to free ART (70% coverage) . AccordiWe conducted this study with the aim of testing the hypothesis that peer support intervention has an impact on virologic and immunologic responses in HIV-infected patients initiated on first-line ART regimens in a rural resource-limited setting in Quang Ninh, Vietnam. This approach will result in evidence-based ART strategies for large populations in low income and low prevalence settings, which will have an impact on HIV treatment guidelines globally.2. Quang Ninh has 14 cities/districts, in which Ha Long City is the biggest . It is also home to the famous World Heritage Site, Ha Long Bay. Coal mining, fisheries, and tourism are the main industries.Quang Ninh province is located along northeastern Vietnam with a population of 1.1 million and an area of 6100 kmHIV prevalence in Quang Ninh was about 1%, of which 55% of PLHIV were IDUs . Patients were recruited from four outpatient clinics (OPC): Ha Long CDC-LifeGap clinic, located in the provincial hospital in Ha Long City and supported by PEPFAR which has more resources, and three Global Fund supported clinics . These were the only clinics in the districts and hence there was a low risk for selection bias from both patients and the project.The cluster randomized controlled trial “Directly Observed Therapy for Antiretrovirals” (DOTARV), registration number NCT01433601 was carried out in 4 districts/cities . The reasons for choosing these 4 districts/cities were: (i) community based care was not available, (ii) these were adjacent districts, and (iii) each had high HIV prevalence. To minimize contamination , the unit of randomization and analysis was the cluster (commune).This trial was conducted between July 2007 through November 2011, with 2 years of patient recruitment and 2 years of follow-up.According to the National Guidelines (2005) , HIV-infAll registered patients received a set standard of care, co-trimoxazole prophylaxis, and were assessed at baseline for socio-economic situations. They were also evaluated clinically, undergoing WHO HIV clinical staging, as well as screening for tuberculosis (TB), viral hepatitis B and C, and opportunistic infections (OIs). Their CD4 counts were taken, and those who were eligible for ART  were put on the waiting list for ART and selected on a “first come, first served” basis. Patients diagnosed with OIs were treated by OI medications. If TB was diagnosed, patients were referred to the provincial TB hospital in Ha Long City. They were initiated on ART after receiving two months of intensive TB treatment. Every month, a range of 15 to 20 patients per clinic, from both groups, were selected, based on the “first come, first served” recruitment list, to attend a pre-ART readiness training on both an individual and group basis. Each clinic received a quota of patients that were planned to initiate ART stipulated by the local health authorities. The training included HIV basics, stigma and discrimination, positive living, transmission prevention, ART regimens and treatment adherence. A family member also attended the training and became an adherence supporter for the patient. ARV drugs were provided in pre-packed dosage form for convenience and to promote adherence. The first-line ARV regimens included two nucleoside reverse transcriptase inhibitors (NRTIs): stavudine (d4T) or zidovudine (AZT) plus lamivudine (3TC) combined with one non-nucleoside reverse transcriptase inhibitor NNRTI: nevirapine (NVP) or efavirenz (EFV). All care and medications were provided free of charge.Patients who participated in the study were selected from the pre-ART waiting list. All patients fulfilling the criteria and planned for ART were asked for their consent to take part in the trial. The patients were informed about the trial by study doctors. The patients, if they agreed to participate, signed the informed consent form. Study doctors would assign patients to either the intervention group or the control group based on the commune where they were living from one of a total of 71 communes in 4 districts. The ratio for intervention: control communes was 36:35 (1:1). The clusters in all four districts were randomized by a statistician who was not involved in the study and were matched according to the following criteria (i) urban vs. rural , (ii) vicinity to the clinic (more or less than 5 km), and (iii) population . The randomization of matched clusters was through a computer software by a statistician not directly involved in the project with no local acquaintance. This study followed an open label cluster randomized controlled trial design.Inclusion criteria were (i) confirmed HIV-infected, (ii) reported as ART-naïve, (iii) resident in any of the four study districts, (iv) age 18 years or older, (v) eligible for ART according to the National Guidelines (2005), CD4 count <200 cells/μl or clinical stage 4, or clinical stage 3 with CD4 count <350 cells/μl, (vi) willing to submit to follow ups and to receive adherence support by a peer-supporter, and (vii) signed a written informed consent.Exclusion criteria were (i) pregnancy or (ii) mental illness.The peer-support intervention strategy was home-based adherence counseling conducted by peer supporters who were HIV-infected individuals on ART and nominated by fellow patients and health care staff at each clinic site. The qualifications needed for peer-supporters were (i) social ability, (ii) good ART adherence for at least 6 months, (iii) high school graduation, (iv) willingness to participate in the study and (v) passed the qualifying test after the training. The OPC’s and local health authorities proposed candidates that fulfilled the selection criteria’s. The proportion of the peer-supporters to the number of recruited patients living in each district was about 1:20, meaning that one supporter would support a maximum of 20 patients. The peer-supporters received 1-week’s training conducted by project researchers on basic HIV care and support, communication and counseling skills, and the process for completing the adherence checklist form. Two 1-week refresher trainings were provided yearly throughout the study.The standard support performed by peer-supporters included home-based visits and completion of the adherence checklist form, in which patients were asked about their wellbeing, OI and adverse drug reaction (ADR) signs and symptoms, the times at which they took the pills, any doses missed for last 4 days, barriers to adherence, and pill count. If an incomplete adherence was reported, the peer supporter would counsel and discuss with the patients and family supporters how to improve the adherence.The initial schedule of support was twice a week in the first 2 months, then once a week when patients’ adherence passed assessments. Additional visits were provided if patients were sick or had a serious ADR or a history of poor adherence. A telephone call was used to arrange a 15- to 30-min appointment place in advance between peer supporters and patients to minimize wasting time or to ensure confidentiality for patients who feared disclosure of their HIV status to others in their surroundings. Due to the associated stigma, the supporters did not wear a work outfit for home visits to minimize the patient’s fear of stigma developing from others in their surroundings. Before being recruited for the study, patients were made aware that being a part of the study would require them to disclose their HIV status. They were warned about the possibility of stigmatization. If patients were not comfortable with that possibility or if they experienced any harm during the study, patients would choose not to be a part of the study. This was monitored during the OPC visits. To ensure satisfactory work by the peer supporters, bi-weekly supervision of peer-support activities was conducted by a peer-support group leader in each district. Monthly supervision meetings of peer-support activities were performed by project researchers.Patients in both intervention and control groups received a set standard of care and treatment according to the National Guidelines  includinThe Exavir™ Load, an enzyme-linked immune-sorbent assay (ELISA)-based VL quantification test , waCD4 counts were run at baseline and every 6 months by the Partec CyFlow® in Uong Bi hospital and the Becton Dickinson® in Quang Ninh provincial hospital.In both the intervention and control groups, patients were assessed by health care staff at the clinic for adherence every 3 months using an adherence checklist modified from the contextualized Adult AIDS Clinical Trials Group (AACTG) adherence instrument . In thisIncomplete adherence was defined as the patient stating in the 3-month adherence checklist form that he or she missed more than one dose  of ARV during the 24 months of their follow-up time.Complete adherence was defined as the patient self-reporting in the 3-month adherence checklist form that he or she did not miss any dose or just one dose (either in the morning or evening) of ARV drugs during the 24 months of their follow-up time.Virologic failure was defined as either (i) primary virologic failure if VL >1000 copies/ml after 6 months of ART initiation or (ii) secondary virologic failure if VL was undetectable (<200 copies/ml) after 6 months of ART initiation and then became >1000 copies/ml at any time point during the follow-up. Virologic failure patients were reported to the attending medical doctors and adherence counselors in their respective clinics. Then a follow-up VL test was repeated after at least one month but within 3 months of the initial virologic failure. If VL remained >1000 copies/ml, the patient was then reported to an OPC doctor and flagged for a confirmatory PCR VL. According to VGHADT (2009) , and incomplete adherence  ; There was no significant effect of intervention on time to virologic failure.p = 0.56] (data not shown).After excluding the 35 ART-non-naïve patients, the statistical analysis among only 605 naïve patients (316 in the intervention group and 289 in the control group) also showed no significant difference in virologic failure risks between intervention and control group  had a significantly lower increase of CD4 count compared to the other patients. On the other hand, patients with an HIV-infected family member had a significantly higher increase in CD4 count compared to those who did not have an HIV-infected family member  : −0.9 ; % CI: −0.The results showed no significant effect of the intervention on the evolution of CD4 count trend between the intervention and control groups.To our knowledge, this is the first randomized controlled trial study in Vietnam to assess the impact of peer support on virologic and CD4 outcomes among HIV-infected patients starting ART. Our study showed a comparably low virologic failure risk, low mortality and high retention rate after 24 months of follow-up. This indicates that a well-funded and organized ART program implemented through PEPFAR and Global Fund in Vietnam can be rolled out successfully in remote and resource-limited settings.After 24 months follow-up, the virologic failure risk in our study (7.2%) was lower than anticipated when the study was planned and compared to other countries (15 to 20%) –33. ThisIn our study, the proportion of virologically suppressed patients on ART at 24 months was 94% which is higher than those reported from other resource-constrained settings including Uganda (86%) , Malawi Despite the fact that the majority of the patients were severely immune-suppressed with low CD4 counts at baseline and half were reported to be at clinical stage 3 or 4, our study showed a lower mortality risk (11% or 6.4/100 person-years) compared to other studies in resourcelimited countries , 42–44. p = 0.7). High retention rates in care indicate not only an improved health care system and ART programs in Vietnam, but also effective care and support activities in the community to motivate and engage patients in care. A recent study in Vietnam conducted among 4531 adults and 313 children showed that 81.2 and 84.4%, respectively, were still on ART after 12 months [The retention rate of patients on ART was 78% after 24 months with no significant difference between the intervention and control groups . Factors that predict the increase of CD4 counts were the VL at baseline ≥100,000 copies/ml, a baseline of CD4 counts <100 cells/μl, and having an HIV-infected family member. In a study in Thailand, CD4 count at baseline and changes in CD4 count were important in predicting CD4 counts ≤200 cells/μl [As shown in our study, CD4 counts responded well after 24 months of ART . This finding is in line with other studies that show how CD4 cell counts increased quickly, in particular after 6 months of ART , 53. Howcells/μl .p >0.05). Also, there was a high discordance (71%) between immunologic and virologic failure. Only 13 patients (29%) had both immunologic failure and virologic failure (p <0.001).In our study, after 24 months we found 45 patients (7%) had immunologic failure, of whom 23 (6.9%) were in the intervention group and 22 (7.1%) in the control group  and incomplete adherence (missing more than one dose during 24 months) were risk factors for virologic failure. High VL  at baseline can be a predictor for the slower increase of CD4 counts and mortality . TherefoThe study results might answer the research question in that there was no significant difference between the intervention and control groups in both cumulative virologic failure risk and time to virologic failure after 2 years of follow-up. This result could be explained in several ways. While the simplest explanation is that peer support inherently does not affect treatment outcomes, we cannot exclude the possibility that our sample sizes may simply have been insufficiently large. With a larger study, we might have been able to gain enough statistical power to discern a difference between the intervention and control groups. Also, the adherence is self-reported, and may have been affected by observer bias. Also, the ART program in Vietnam has been well funded and implemented through international donors including PEPFAR and Global Fund. Before ART was initiated, each patient had to be assessed for ART readiness, name a supporting family member and attend three adherence counseling sessions according to the National Guidelines . FurtherIn addition, patient support could have originated from a number of different sources that may have contaminated the study including the OPCs and the community-based programs. Quang Ninh province, with a comparably high HIV prevalence, was receiving PEPFAR support in order to set up “comprehensive care, treatment and support” programs with NGOs, which were very active during the time of the project implementation. The availability of community-based activities provided by “the Bright Future” and other community outreach groups might have constituted a “contamination” where patients in the intervention group could meet and share adherence experiences with patients in the control group.Furthermore, IDU in both the control and intervention groups had incentives to remain on the treatment regimens. Active IDUs may get arrested and placed into a drug rehabilitation centers. The risk of this may be increased if they fail to follow the treatment schedule, and thereby get attention from authorities. IDUs also received further counseling at the OPC and, for those in the intervention group, from the peer supporters.In our study, 400 (63%) patients lived with their parents and other family members who might also play an important role as “internal supporters” to support patients in taking ARVs. Vietnamese culture strongly values the care of the extended family members, so most patients had good support for adherence from their families.In our study, we only reported data to the 24-month-follow-up; hence the sustained or longterm effect of the adherence support intervention cannot be excluded. It should be noted that as patients started their ARV and improved their health, their perceived need for peer support may have declined. It was also apparent from discussion with peer supporters and patients that the personal relationship between the patient and supporter was crucial for long term peer support and follow up. Many patients saw the benefit and developed a close bound to their peer supporter, sometimes too close from the peer supporter’s point of view. In other cases, the patients perceived the support as an annoyance. A recent study in Uganda has also shown that peer health care intervention had no impact on cumulative risk of virologic failure and virologic outcomes on short-term ART and suggested that it might be best suited for patients who have taken ART for longer periods, especially as it may mitigate the effects of “treatment fatigue” as patients tire of continually taking ART . TherefoDespite the results showing peer support had no significant effect on virologic failure, it is nevertheless clear that good outcomes can be achieved in resource-limited communities. The support the patients received may still be considered a global standard of care.This is the first cluster randomized controlled trial on HIV conducted in a rural setting in Vietnam. We had some limitations and constraints in logistics, in recruiting patients, collecting data, and analysis due to a lack of precedence to follow. It took 2 years for recruiting enough patients instead of 10 months that we had originally planned. There were 35 (6%) patients who were ART-non-naïve. However, as the study was intention-to-treat and the non-naïve status was revealed after enrollment, these cases were still included in the study and the results might not represent whole treatment-naïve population. Patients in both groups may receive other community-based supports that might be a “contamination”. In addition, patients in the intervention group could meet and share adherence experiences with patients in the control group at the clinic . Some patients were willing to move or even travel long distances in order to receive treatment from a certain clinic. This devotion to obtaining ARV could have contributed to the high adherence in both groups. The CD4 counts were done in two different hospital laboratories which may bias the estimation of immunologic failure. As the clusters were randomized before the recruitment of patients and the selection process of the patients should have randomized the individual clusters, the difference in the number of patients in each arm is unlikely to lead to bias. A limitation in our study was that the adherence data collected from peer supporters during their patient encounters in the intervention group wasn’t included in the analyses.ART programs in resource-limited rural settings like Quang Ninh, Vietnam can provide an effective care and treatment with a low virologic failure risk if the patients are well-prepared for ART and followed up regularly by an out-patient clinic. Peer support to improve adherence did not show any impact on virologic failure and CD4 trends during first 2 years of ART. High VL at baseline is a predictor for virologic failure and CD4 trends.


The serum gradient of hepatitis B surface antigen (HBsAg) varies over time after cessation of nucleos(t)ide analog (NA) treatment in patients with chronic hepatitis B (CHB). The association between the time-varying HBsAg serum gradient and risk of relapse has not been elucidated.n = 140) were followed every 3 months through HBsAg quantification. Virological and clinical relapses were defined as viral DNA levels >2000 IU/mL and alanine aminotransferase (ALT) levels >80 U/mL, respectively. The association of time-varying HBsAg levels with relapses was assessed through a time-dependent Cox analysis.This multicenter cohort study prospectively enrolled CHB patients who discontinued 3 year-NA treatment. Eligible patients were serologically negative for HBeAg and viral DNA at NA cessation. The participants (P < 0.001) and clinical (P = 0.01) relapses in a dose–response manner, with adjusted hazard ratios of 2.10  and 2.32 . Among the patients (n = 19) whose HBsAg levels ever dropped below 10 IU/mL, only one and three patients subsequently developed clinical and virological relapses.During a median follow-up of 19.9  months, virological and clinical relapses occurred in 94 and 49 patients, with a 2-year cumulative incidence of 79.2%  and 42.9% , respectively. The serum level of HBsAg was associated with virological (The serum gradient of HBsAg measured throughout the off-therapy observation is associated with the subsequent occurrence of virological and clinical relapses in CHB patients who discontinue NA treatment. Chronic infection with hepatitis B virus (HBV) is the leading cause of liver-related morbidity and mortality worldwide, particularly in Asian countries . ManagemBecause of high off-therapy relapse rates, major international guidelines currently recommend an indefinite prolongation of NA therapy, possibly until loss of hepatitis B surface antigen (HBsAg) with or without appearance of accompanying antibodies . HoweverIn response to the challenges associated with the safe discontinuation of NAs, we prospectively followed a multicenter cohort who discontinued NAs after a minimum of 3 years on therapy. We observed that the serum gradient of HBsAg observed at the end of treatment (EOT), in addition to serum alanine aminotransferase (ALT) levels and age, stratified the risks of both virological and clinical relapses . After tThis prospective cohort study was conducted in three different regional teaching hospitals  in Taiwan. Institutional review boards approved the study protocol (EMRP100–049) in all hospitals for patient recruitment and database establishment. Data analysis specifically for this study was also approved (EMRP-104-082). Written informed consent was obtained from all participants prior to their enrollment.We consecutively screened adult patients with CHB who were going to discontinue NA therapy between July 1, 2011 and April 1, 2015, and we evaluated their eligibility. Patients were included if they had been diagnosed with CHB for at least 6 months prior to NA treatment, continuously received any NA  for at least 3 years, were serologically negative for HBeAg, and showed undetectable levels of HBV DNA at the end of NA therapy. Patients were excluded in the presence of coinfection with human immunodeficiency virus or hepatitis C virus, any malignancy, liver cirrhosis, hepatic encephalopathy, variceal hemorrhage, organ transplantation, previous use of interferon alpha for 1 month or longer, and concurrent use of cytotoxic or immunosuppressive medication. The diagnosis of liver cirrhosis was based on pathological proof or clinical criteria that included splenomegaly or esophagogastric varices in addition to typical sonographic features.10 In brief, the therapeutic duration was principally restricted to 3 years among general patients without cirrhosis. Those who experienced HBeAg seroconversion on therapy were entitled to treatment consolidation for an additional 1 year.Patients had to discontinue NAs because of the national health insurance policy. Details of the reimbursement regulations have been previously reported.Pertinent demographic, biochemical, serological, and virological data were collected at enrollment. After discontinuation of NAs, patients were monitored at a close interval of 3 months. The patients underwent physical checkup and laboratory measurement at each follow-up visit. They also underwent abdominal sonography along with serum alpha-fetoprotein estimation tests every 6 months for the surveillance of liver cancer.8 IU/mL.Standardized quantification of serum HBsAg and viral DNA was carried out in the Taipei Pathology Institutes . Serum HBsAg levels were measured through an automated immunoassay . Samples with HBsAg levels exceeding the upper limit of automatic detection (250 IU/mL) were manually diluted before quantification. Serum HBV DNA was quantified through a commercialized polymerase chain reaction method  with a detection range of 20–1.7 × 10Virological relapse was defined as the reappearance of >2000 IU/mL HBV DNA in serum. Clinical relapse was defined as an episode of elevated ALT  and >2000 IU/mL HBV DNA. Patients did not resume antiviral therapy until clinical hepatitis persisted for 3 months or longer, unless a risk of hepatic decompensation (serum bilirubin >2 mg/dL or prothrombin time prolonged >3 s) was observed.P < 0.05.Continuous and categorical variables were summarized using the median and interquartile range (IQR) and proportion with exact numbers, respectively. The incidence rates of virological and clinical relapses were estimated using the Kaplan–Meier method. In a multivariate-adjusted Cox proportional hazards model for off-therapy relapses, the serum level of HBsAg was a time-varying variable that denoted each measurement after NA cessation. The dose–response relationship for the association between HBsAg levels and off-therapy relapses was illustrated by penalized splines in the Cox model. The results were reported as hazard ratios along with 95% confidence intervals (CIs). Data were analyzed using commercial software . All statistical analyses were two-sided with significance set at n = 109) with a median age of 49.1  years. Prior to antiviral treatment, 39 patients were initially HBeAg-positive. They were all serologically negative for HBeAg after treatment and had been consolidated for at least 1 year  following HBeAg loss. The median levels of HBsAg, ALT, and alpha-fetoprotein were 2.79  log IU/mL, 22  U/L, and 2.7  ng/mL at the end of treatment, respectively.We monitored a total of 140 patients who discontinued NA therapy after a minimum of 3 years  between July 1, 2011 and April 1, 2015  and 42.9%  at 1 and 2 years, respectively, and those of virological relapses were 62.0%  and 79.2%  at 1 and 2 years, respectively (Table P = 0.00017) and clinical (P = 0.012) relapses. Moreover, no obvious nonlinearity was observed in the dose–response relationship, supporting the use of a linear term in the Cox model to summarize the hazard ratio for one log increase in the HBsAg level.The penalized splines in the univariate Cox model characterized the dose–response curves between increments of HBsAg and risks of relapse Fig. . An incrP = 0.19 for virological and 0.71 for clinical relapses), thus satisfying the proportional hazard assumption for the model.The association between time-varying serum levels of HBsAg and off-therapy relapses was further examined through the multivariate-adjusted Cox proportional hazard analysis, which revealed that HBsAg levels, EOT age, and EOT ALT were significant predictors of both clinical and virological relapses. For virological relapse, the serum level of HBsAg, EOT age, and EOT ALT were associated with adjusted hazard ratios of 2.10 per log IU/mL , 1.04 per year , and 1.02 per U/L , respectively (Table P < 0.0001), compared with those whose HBsAg levels never fell below10 IU/mL.The predictive value of low HBsAg was demonstrated by 19 patients whose respective HBsAg levels ever dropped below 10 IU/mL during the off-therapy follow-up. Among them, only one and three patients subsequently developed clinical and virological relapses, respectively . Another study involving 252 patients in southern Taiwan [Inactive carriers have been found to have low HBsAg levels –25, withn Taiwan  also shoAlthough patients subjected to NA treatment had a favorable response with regard to HBV DNA levels, the observed HBsAg decline in such patients was lower than in those treated with interferon. This is probably due to the mechanism of NA treatment. NA treatment affects the reverse transcription of pregenomic RNA, but it does not affect covalently closed circular DNA and subgenomic RNA, which have translational activities associated with HBsAg levels . MoreoveIn the current strategies of NA-off follow-up, the HBV DNA and ALT would be monitored routinely and closely. However, elevation of ALT is usually a late event preceded by viral rebound and cannot be regarded as an early predictor. Following abrupt resurgence of viremia, severe acute exacerbation could rapidly ensue and incur the risk of liver failure. Besides, measurement of viral DNA remains costly. Our study showed the HBsAg kinetics has a linear association with relapse risks. Therefore, HBsAg level monitoring, every three months for instance, provides a chance to identify those who may not need frequent viral DNA measurement, and implicates a safe follow-up strategy with less expense.This study has several strengths. First, we monitored HBsAg levels during the entire follow-up instead of at a single time point. Second, this research was conducted in a real-world setting that reflects “in-field” practice. For external validity, patients were recruited from multiple sites and treatment was not restricted to a single NA. Third, a minimum of 3-year NA therapy enabled most patients to obtain remission status before discontinuing NAs. Finally, stringent monitoring with an interval of 3 months enabled us to observe both virological and clinical relapses closely.Several limitations were noted in this study. First, because this study prospectively started after NA discontinuation, blood samples prior to the baseline were unavailable. Therefore, we could not ascertain when HBV DNA became undetectable during the treatment by using a standardized protocol. We acknowledge that this is a major limitation because the length of consolidation following remission of viremia has been shown to influence the risk of relapse . NonetheIn conclusion, this study reveals a dose–response association between time-varying HBsAg and off-therapy relapse following the cessation of NA therapy in patients with CHB. By reporting a negligible risk of subsequent relapse in patients whose HBsAg dropped to a considerably low level (<10 IU/mL), we demonstrate the potential utility of monitoring HBsAg levels in patients with CHB who discontinue NA treatment. These findings may not only implicate a safe strategy to monitor patients who attempt NA cessation but also stimulate further research to elucidate the clinical relevance of HBsAg quantification.


Generic drug policies are often associated with concerns about the quality and effectiveness of these products. Phase IV clinical trials may be a suitable design to assess the effectiveness and safety of generic drugs. The objective of this study was to describe the effectiveness and the safety of the generic abacavir/lamivudine and efavirenz in treatment-naïve HIV-infected patients.A monocentric, nonrandomized, open-label, phase IV study in treatment naïve HIV-infected patients 18 years or older with indication to receive abacavir/lamivudine and efavirenz were recruited from a program that provides comprehensive outpatient consultation and continuing care. The primary end-point was to achieve viral load <40 copies/mL at 12 months after baseline to assess effectiveness. Secondary end-point of the study were 1) to asses increasing in T-CD4 lymphocytes levels as accompaniment to asses effectiveness, and 2) to assess both gastrointestinal, skin, and central nervous system symptoms, and lipid profile, cardiovascular risk, renal, and hepatic function as safety profile. Data were determined at baseline, 3, 6, and 12 months. Close clinical monitoring and pharmaceutical care were used for data collection. Wilcoxon matched-pairs signed-rank test was used to compare proportions or medians.3) in the median for CD4 T lymphocyte count. The adverse events were mild and met the safety profile for this antiretroviral regimen, mainly of central nervous system symptoms, skin rash, lipid abnormalities, and an increase of 2 % in the median of the percentage of cardiovascular risk.Sixty patients were invited to participate in the study; 42 were enrolled and 33 completed the follow-up. Of the nine patients excluded from the study, only one was withdrawn due to adverse events. At 12 months, 31 of 42 patients  achieved a viral load of HIV1 RNA <40 copies/mL. There was a significant increase  ID:  Substantial progress has been made in the prevention and treatment of HIV/AIDS but it remains a public health challenge. A report on the global AIDS epidemic 2013 informed that in 2012 there were 35.3 million people living with HIV, 2.3 million new infections, and 1.6 million AIDS-related deaths ) and situations in which the use of medicines caused or might cause the appearance of a NOM (drug-related problems). If necessary, lifestyle interventions to improve adherence and/or use of drug therapy were implemented.Completed a new assessment form. Completion of an intervention should have generated a change in the patient’s assessment. Depending on whether a NOM still existed, the therapeutic plan was completed.The DADER method for pharmaceutical care is a systematic process developed by the Research Group of Pharmaceutical Care at the University of Granada, Spain. The intervention is based on the use of pharmacotherapy records, evaluation of an assessment form that includes all HIV/AIDS health problems and the drugs used to treat these medical problems, and their assessment on a specific date. Thus, pharmacists did the following , 21:ObtaDo you ever forget to take your medicine?Are you careless at times about taking your medicine?Sometimes if you feel worse, do you stop taking your medicines?Thinking about the last week. How often have you not taken your medicine?Did you not take any of your medicine over the past weekend?Over the past 3 months, how many days have you not taken any medicine at all?ARV drugs were dispensed monthly and patient drug adherence was assessed using a simplified medication adherence questionnaire (SMAQ), an indirect method that has been validated in patients with HIV . The SMAPatients were classified as non-adherent if they replied to any of the questions with a non-adherence answer. For quantification of omissions, patients were classified as non-adherent if they lost more than two doses during the previous week or had not taken medication for more than 2 complete days during the previous 3 months. Patients who were classified as non-adherent were excluded from the study.To minimize potential biases, all blood samples were handled in the same manner and analysis was performed by the same certified laboratory using validated techniques. The ARV drugs, with their respective quality assurance certifications, were provided by Humax Pharmaceutical S.A.p < 0.05 was considered statistically significant.Statistical analyses were performed using STATA/IC 13.1 . An exploratory data analysis was used to calculate the central tendency measures, dispersion, frequency tables, 95 % confidence intervals, and normality tests. Data were reported as percentages or medians [quartile 1 (Q1)–quartile (Q3)]. Wilcoxon matched-pairs signed-rank test was used to compare proportions or medians. Comparisons were analyzed using two-tailed tests, and The primary analysis was the proportion of patients who viral load <40 copies/mL at 12 months after baseline to assess effectiveness. Both intention to treat (ITT) analyses  and on treatment (OT) analyses (consider only the subjects who fulfill completed the 12 months of followed) were used to analyze the results.Declaration of Helsinki” and its amendments, and the Guide to Good Clinical Practice (ICH E6). Informed consent was obtained from each participant before inclusion in the study. The study was approved by the medical ethical committee from the institution participating .The study was conducted according to the ethical principles regarding human experimentation established in Colombia by both Resolutions 8430 of 1993 and 2378 of 2008, as the “A flowchart of the patients involved in the Cali-Colombia generic drug study is shown in Fig. 3 vs. 545 (439–634) cells/mm3, (p <0.001)], and of 12.9 % in median (Q1–Q3) of %CD4 . Similarly, there was a statistically significant increase in the CD4 T-lymphocyte count/CD8 T-lymphocyte count ratio above 0.5.Regarding effectiveness at 12 months, 31 of 42 patients—73.8 % in intention-to-treat analysis; and 31 of 33 patients—93.9 % on-treatment analysis—achieved a viral load of HIV1 RNA <40 copies/mL , HDL-C, and triglycerides. There was a significant increase of 2 %, in the median of the percentage of CV risk score, according to the Framingham equation (from −1 % to 1 %); however, at 48 weeks the CV risk score for 33 patients continued to be valued as lower risk, and only 1 patient was assessed as 10 % of CV risk , both the baseline median CD4 count (Q1–Q3) [225 (103–324) cells/mm3] and the baseline median HIV-1 RNA level (Q1–Q3), [4.7 (4.3–5.0) log10 copies/mL] different notorious from our baseline values median CD4 count (Q1–Q3) [373 (326–483) cells/mm3] and median HIV-1 RNA level (Q1–Q3) [(4.3 (3.9–4.7) log10 copies/mL].Ideally, it would be to compare the change form baseline CD4 cells/mmnditions . Thus, wnditions –27. Howeator arm . For insator arm , in the 3) in the median for CD4 T lymphocyte count , skin rash 14.3 %), and drowsiness (11.9 %)  and non-adherence to ARV drugs (four patients) did no drug-related treatment. A total of 37 adverse events considered related to the study were reported for the 42 patients but cART only was the cause of withdrawal for just one patient, 2.4 % (1 of 42). Compared with other studies that used ABC/3TC and EFV proprietary scheme, this value is lower than 4.9 % (16 of 324 patients) , 10.7 % n = 178 patients at baseline) [Both ABC/3TC , 36 and aseline)  there waThe increase in the CV risk may be proportional to the increase in TC levels, LDL-C, and triglycerides. However, ABC has been associated only to slight increase of the CV risk, and more important the data related to ABC, as a cause of myocardial infarction, remain inconclusive and controversial. In this way, some studies have concluded that an increased risk of myocardial infarction exists in patients exposed to ABC in the preceding 6 months  and it hThis study provides important elements for evaluation regarding the effectiveness and safety of generic ARVs produced in Colombia. Phase IV clinical trials could be an important option to assess and support the quality of generic drugs used in standardized clinical practice . Our finEfforts are need to reduce drug costs through increased use of generic drugs, price negotiation, and public health directives such as compulsory licensing . ColombiBecause our study had several limitations, the results and conclusions should be interpreted with caution. First, this study was based on a small sample of HIV/AIDS treatment naïve patients who were followed for only 12 months. Thus, the small sample size could be insufficient to obtain strong conclusions. However, the current study may prove clinical information about effectiveness and safety of ABC/3TC and EFV generics, which has been considered as scarce . Second,In a small group of HIV-infected treatment naïve patients followed for 12 months, this open-label, nonrandomized study showed that, as expected, the clinical outcomes of generic drug version of ABC/3TC and EFV were compatible with the safety and effectiveness profile of proprietary ARV drugs.


We aim to evaluate the overall survival and associated risk factors for HIV-infected Chinese patients on antiretroviral therapy (ART). 2517 patients receiving ART between 2006 and 2016 were prospectively enrolled in Yunnan province. Kaplan-Meier analyses and Cox proportional hazard regression analyses were performed. 216/2517 patients died during a median 17.5 (interquartile range [IQR] 6.8–33.2) months of follow-up. 82/216 occurred within 6 months of starting ART. Adjusted hazard ratios were10.69  for old age, 1.94  for advanced WHO stage, and 0.42  for heterosexual transmission compared to injecting drug users. Surprisingly, adjusted hazard ratios comparing low CD4 counts group (<50 cells/µl) with high CD4 counts group (≥500 cells/µl) within six months after starting ART was 20.17  and it declined to 3.57  afterwards. Age, WHO stage, transmission route are significantly independent risk factors for ART treated HIV patients. Importantly, baseline CD4 counts is strongly inversely associated with survival in the first six months; whereas it becomes a weak prognostic factor after six months of starting ART. Despite of a low national prevalence rate, the HIV epidemic is severe in some areas of the Southwest China, in particular the Yunnan, Sichuan, and Guangxi provinces. Yunnan is the area most affected by HIV/AIDS in China. The epidemic has spread from high-risk groups including drug users, sex workers and unsafe blood recipients to the general population. With a population of 44 million, officials estimate that this province has 80,000 HIV infected individuals. Antiretroviral drugs in combination of three or more drugs from more than one class, often called “highly active antiretroviral therapy (HAART)”, are very effective in suppressing HIV, although do not eradicate the virus. Since the first introducing of HAART in the mid-1990s, it has led to an unprecedented decline of mortality caused by HIV/AIDS both in the USA2 and Europe3. Because of the great success of HAART in treating HIV/AIDS in the developed countries, the World Health Organization (WHO) has promoted a public health approach to scale up the access of antiretroviral therapy in resource-limited setting since 20025. As an emergency response to save and improve the lives of AIDS patients in China, the China National Free Antiretroviral Treatment Program (NFATP) was piloted in 2002 and scaled up in 2003 national wide7. Until 2014, a total of 295,358 patients in China have received HAART1, and thus a large proportion of HIV patients have benefited from this program. Based on China national HIV database as well as a few local studies, an increasing coverage of antiretroviral treatment has significantly decreased HIV/AIDS-related mortality12.As estimated by the Chinese health authority21. According to those results, the prognostic value of CD4 cell count seems to be well-established. However, a recent study, examining European and North American patients, suggested that patients with low baseline CD4 cell count only carry the burden of increased risk of death up to 5 years after ART16. This indicated the impersistence of the CD4 cell count on the increased mortality, although no other study has reported similar observation. In order to better understand the treatment outcome of HIV patients, we have carried out a large prospective cohort study with long-term follow up in China, enrolling patients from Zhaotong, a prefecture-level city located in the northeast corner of Yunnan province. In this study, we aim to evaluate the overall survival and associated risk factors for the HIV-infected patients on ART in this cohort, with particular focus on the prognostic value of CD4 cell count.It is important to identify prognostic factors for survival among HIV-infected patients receiving ART. Based on previous studies, the main risk factors for death include baseline low CD4 cell count, old age and advanced WHO stage. Among them, CD4 cell count was suggested as the most important prognostic factor based on the estimated hazard ratio valuesA total of 2517 patients (adult) before starting ART were enrolled between July 2006 and April 2016 in this study. The baseline characteristics of the study population at start of ART are summarized in Table The crude cumulative mortality for study population is displayed in Fig. The associations of baseline factors at start of ART with mortality, estimated from crude and adjusted Cox models with time-dependent coefficients for CD4 cell count are shown in Table This is a large prospective study pioneering the assessment of patient survival and associated risk factors in Chinese population with HIV infection receiving ART. We described the treatment outcome and identified baseline age, WHO clinical stage as independent predictors for patients survival for all time. The low CD4 cell count at baseline had a strong inverse association with survival at first six months of starting ART.3. A high tolerance of ART regimen and fewer regimen switches were found among our patients  and low CD4 cell count compared with the entire study population. Thus, poor baseline patient characteristics seem to contribute largely to the worse survival, supporting the importance of early diagnosis and treatment25. Overall, we feel that the first six months of ART is critical for improving survival outcome in HIV-infected patients.The survival benefit from ART have been demonstrated intensively among the HIV infected patients27. A potential reason could be the lack of testing the proportional hazard assumption for Cox model, or such assumption was met in those studies. Another potential explanation could be the relatively short follow-up time in many previous studies. Taking this into consideration, a recent retrospective study with long-term follow-up (more than ten years) from the Antiretroviral Therapy Cohort Collaboration (ART-CC) have suggested that the baseline CD4 cell count is less prognostic after five years since starting ART16. In other words, the patients with low baseline CD4 cell count, who survived the first five years since ART, may expect similar mortality to that of patients with high baseline CD4 cell count. In our prospective cohort study, a strong inverse association between baseline CD4 cell count and risk for mortality was also observed, but only for the first half year after starting ART. We observed a 10-fold increased mortality for low CD4 cell count, which was much higher than the 2.8-fold increase in the ART-CC study16. Of note, there are several differences between these two studies, in particular European Americans vs Chinese population. Another important difference to be noticed is the anti-HIV drugs used in those studies. The patients engaged in the ART-CC study received ART between 1996 and 2001; however, our patients have been treated since 2006 with the newer anti-HIV drugs. Given the fact that new drugs introduced since 2002 provide a better immunological response29, our data might reflect more the treatment effect on HIV infected patients nowadays. These factors may contribute to the discrepancies observed between our study and the previous ones. Besides, the CD4 cell count at six months after starting ART was also examined in our study for assessing its potential association with survival after six months of starting ART. In contrast to values at baseline, the six-month CD4 cell count was strongly associated with the worse survival for the period after six months of ART initiation. Consistently, the prognostic value of six-month CD4 cell count has been demonstrated previously30. To be noticed, due to the missing values of six-month CD4 cell count among the patients who had survived for six months , including Zhaoyang District, Ludian County, Qiaojia County, Yanjin County, Daguan County, Yongshan County, Suijiang County, Zhenxiong County, Yiliang County, Weixin County and Shuifu County. All patients were treated based on the criteria of the “National AIDS Free Antiviral Treatment Manual”, HIV drug resistance, individual health, and other factors. We collected data on demographics , histological parameter , and laboratory maker (CD4 cell count) at baseline when patients initiated ART.The institutional ethical committee of the First Affiliated Hospital of Kunming Medical University has approved this study. Informed consent was obtained from all participants in this study. No personally identifiable information was seen and used in our data analysis. All the methods of this study were performed in accordance with the guideline and regulation of the institutional ethical committee of the First Affiliated Hospital of Kunming Medical University.All patients were followed up from the date since starting ART until the date of death, loss to follow-up, or the end of follow-up. Patients who were lost to follow-up or the event did not occur within the study duration were considered as censored cases. For the patients with treatment changes or interruptions, we analyzed the data as their intent to continue treatment, same as the other patients.35. All statistical analyses were performed in R (version 3.3.1)36. Particularly, “survival” package37 was used for survival analyses. The loss to follow up and not loss to follow up against survival time were plotted to depict the their patterns  was considered as significant. The R code for performing Cox proportional regression analyses in this study is shown in Supplementary Figure In descriptive statistics, continuous variables were reported as mean with standardized deviation (SD) and median with interquartile range (IQR). Categorical variables were reported as number with percentage. A crude survival analysis (Kaplan-Meier curve) was utilized to analyze the patients’ survival on ART during 10-year follow up. An adjusted survival analysis, Cox proportional hazard regression analysis, was used to evaluate the factors related to survival outcome. Variables with a p-value below 0.20 on univariate analysis were included in multivariate analysisThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Supplementary info


The international and national HIV treatment guidelines in 2016 have focused on scaling up access to combination antiretroviral therapy (cART). We aimed to assess the trends and treatment outcomes of late cART initiation in Taiwan.3 or having experienced AIDS-defining illnesses. The treatment outcomes were assessed up to 6 months after starting cART.Between June 2012 and May 2016, we retrospectively included antiretroviral-naive HIV-positive adults who initiated cART. Late initiation was defined as when cART was initiated in patients with a CD4 count <200 cells/mm3 in 2012 to 298 cells/mm3 in 2016, and the overall proportion of late cART initiation decreased from 49.1% in 2012 to 29.0% in 2016 (P for trend <0.001). Late cART initiation mainly resulted from late presentation for HIV care and was associated with older age , HBsAg seropositivity , HIV care in central and southern Taiwan, initiating cART in earlier year, non-intravenous drug users , and negative hepatitis C serostatus . Compared with non-late initiators, late initiators had a higher rate of all-cause mortality (1.7% vs. 0.3%) and regimen modification due to virological failure (7.1% vs. 2.6%). The predicting factors of all-cause mortality were late cART initiation  and older age .We included 3655 HIV-positive patients, and the majority of the patients were male (95.4%) with a median age of 31 years and initiated non-nucleoside reverse-transcriptase inhibitor-containing regimens (87.0%). The median CD4 count at cART initiation increased from 207 cells/mmWhile the proportion of late cART initiation decreased over time in Taiwan, late initiation remained in a substantial proportion of HIV-positive patients. The late initiators had higher risk for poor outcomes. The need for strategies to earlier detection of HIV infection and expediting cART initiation should be highlighted, especially among the older population. The scale-up combination antiretroviral therapy (cART) helps reduce AIDS-related deaths and new HIV infections, as well as decrease further expenses for medical services . The glo3 in 2011 [Many countries in the Asia-Pacific region have made great strides in accessing cART through their HIV treatment guidelines and programs, and the region’s treatment coverage rate has increased from 19% in 2010 to 41% in 2015; however, the coverage rate still lagged behind the global coverage rate –8. WhileThese previous findings may not be generalized across all Asia-Pacific countries, however; whether the national HIV treatment programs get HIV-positive patients treated earlier may rely on regional studies. In Taiwan, a high-income country according to the World Bank classification , HIV-relWe conducted a retrospective cohort study at 11 major designated hospitals for HIV care that participated in the Taiwan HIV Study Group. We included all HIV-positive patients aged 20 years or greater who were antiretroviral-naïve and initiated cART between 1 June 2012 and 31 May 2016. Patients without baseline CD4 cell count before cART initiation were excluded. Data was collected locally at each participating hospital, and then pooled and analyzed at the National Taiwan University Hospital. The study was approved by the Research Ethics Committee of National Taiwan University Hospital, Research Ethics Review Committee of Far Eastern Memorial Hospital, Medical Ethics and Institutional Review Board of Taoyuan General Hospital, and Institutional Review Boards . The informed consent was waived.3 in September 2013 [The Taiwan Centers for Disease Control (CDC) has provided HIV-positive patients with free-of-charge medical services, including cART, management of opportunistic illnesses, and laboratory testing, including monitoring of CD4 cell count and plasma HIV RNA load (PVL). Genotypic resistance assays were neither offered free-of-charge or routinely determined before cART initiation, although surveillance data suggested that the prevalence of transmitted drug resistance of HIV-1 to at least one antiretroviral was in the range of 10–15%; instead, the assays were performed at Taiwan CDC or a few designated hospitals for patients with virological failure and PVL >1000 copies/mL –14.The nber 2013 , which w3 or having experienced AIDS-defining illnesses before cART initiation [We collected the information on demographics and clinical characteristics, such as age, sex, mode of HIV exposure, hepatitis B virus (HBV) surface antigen (HBsAg), hepatitis C virus (HCV) antibody, baseline CD4 cell count and PVL at cART initiation and serial follow-up visits, AIDS-defining illnesses before cART initiation, dates of cART initiation and loss to follow-up, and initial and switched antiretroviral regimens. The baseline CD4 cell count and PVL were defined as the data prior to and nearest to the date of cART initiation. Late initiation of cART was defined as when cART was initiated in patients with a baseline CD4 cell count <200 cells/mmitiation , 16.3, or PVL <100,000 versus ≧100,000 copies/mL. Within 6 months after initiating cART, patients returned for assessment of virological, immunological, and clinical responses at week 4, and subsequently every 8 to 12 weeks [The treatment outcomes were assessed at 6 months and comparisons were made between HIV-positive patients with and without late cART initiation, and those initiating cART at CD4 cell count <500 versus ≧500 cells/mm12 weeks . The treP <0.05 was considered statistically significant. Statistical analyses were performed using Stata software version 12.0 .Categorical variables were analyzed using the Chi-square test or Fisher’s exact test if the expected values were <10. Continuous variables were compared using the Wilcoxon-Mann-Whitney test. The trend analyses were evaluated by the generalized linear model and Cochran-Armitage trend test for continuous and categorical variables, respectively. The factors associated with late cART initiation were identified by logistic regression model. The predictors of all-cause mortality and regimen modification were determined by Kaplan-Meier survival estimations and Cox proportional hazards model. All variables in univariate analyses were selected for subsequent multivariable analyses. Ninety-five percent confidence intervals (CIs) of odds ratios (ORs) or hazard ratios (HRs) were computed to estimate the effects of each variable. All tests were two-tailed and Table 1. Most patients were male (95.4%) with a median age of 31 years and men who have sex with men (76.9%) and received HIV care at designated hospitals in northern Taiwan (70.9%). Approximately 10% and 20% of the patients were HBsAg-positive and anti-HCV-positive at cART initiation, respectively. The overall median baseline CD4 cell count was 270 cells/mm3 , and 13.2% of the patients had experienced AIDS-defining illnesses before cART initiation. Half (50.6%) of the patients initiated cART before the first half year of 2014, and approximately 87.0% started nNRTI-containing regimens.During the 4-year study period, 3655 HIV-positive Taiwanese patients initiating cART were included. The demographics and clinical characteristics of all included patients are summarized in 3. The median duration between HIV diagnosis and cART initiation was 1.6 months  in these patients. The interval between HIV diagnosis and cART initiation according to the year of HIV diagnosis decreased from 3.5 months in 2012 to 0.5 months in 2016.Among those 3655 included patients, the dates of and CD4 cell counts at HIV diagnosis were available in 953 patients (26.1%), in whom 340 (35.7%) presented for HIV care with CD4 cell counts <200 cells/mmFig 1. The median CD4 cell count significantly increased from 207 cells/mm3 for the patients initiating cART in the second half year of 2012 to 298 cells/mm3 for those in the first half year of 2016 (P for trend <0.001). The CD4 cell counts were classified into 4 groups: <200 cells/mm3, 200–349 cells/mm3, 350–499 cells/mm3, and ≧500 cells/mm3. In the second half year of 2012, the majority of the patients (47.7%) initiated cART with a CD4 cell count <200 cells/mm3; in contrast, more than one-third of the patients (38.4%) started cART with a CD4 cell count ≧350 cells/mm3 in the first half year of 2016. While the proportions of baseline CD4 cell counts between 350–499 cells/mm3 and ≧500 cells/mm3 from 2013 onwards were significantly higher than those in 2012, the proportions of CD4 cell counts between 200–349 cells/mm3 and <200 cells/mm3 decreased over time (P for trend <0.001). However, there were still 30% of the patients who initiated cART late with CD4 cell counts <200 cells/mm3 in the most recent study year. In addition, the median CD4 cell counts had no significant change among patients aged 50 years or greater, among whom the median CD4 cell count was 130 cells/mm3 in the second half year of 2012 and 165 cells/mm3 in the first half year of 2016.The trends of median CD4 cell counts at cART initiation that were assessed over each 6-month study period are shown in Fig 2, the proportion of the patients with late cART initiation had significantly declined from 49.1% in the second half year of 2012 to 29.0% in the first half year of 2016 (P for trend <0.001). However, the percentage of the patients having AIDS-defining illnesses prior to cART initiation remained at more than 10% till the first half year of 2016, without statistically significant difference compared with those of previous study years (P for trend = 0.082).Among the 3655 patients, 1278 (35.0%) initiated cART late and 2377 (65.0%) did not. In Table 1. The patients with late cART initiation were older and more likely to be heterosexual, seropositive for HBsAg, and seronegative for HCV antibody, and to receive HIV care at hospitals in central and southern Taiwan. They also tended to have lower baseline CD4 cell counts and higher PVL, and started cART in the earlier years . In multivariable analysis, the factors associated with late cART initiation were older age , receiving HIV care at hospitals in central and southern Taiwan , and HBsAg seropositivity . Late cART initiators were more likely to be non-intravenous drug users (IDUs)  and to test negative for anti-HCV . In line with the aforementioned trend analysis for baseline CD4 cell count, there was a statistically significant association between non-late cART initiation and initiating cART in later years, which strengthened over time during the study period (Table 2).The demographics and clinical characteristics of the patients stratified by late and non-late cART initiation are shown in Table 3, while the comparisons between patients initiating cART at CD4 cell counts <500 versus ≧500 cells/mm3 are shown in S1 Table. All-cause mortality occurred in 22 (1.7%) and 6 (0.3%) patients in the late initiation and non-late initiation groups, respectively. The estimated HR for all-cause mortality in the late initiation group was 6.86  compared with the non-late initiation group in univariate analysis . However, the difference in all-cause mortality between the patients initiating cART at CD4 cell counts <500 and those at CD4 cell counts ≧500 cells/mm3 did not reach statistical significance  . In multivariable analysis, late cART initiation remained statistically significantly associated with all-cause mortality. The other independent predictor of all-cause mortality was older age  (Table 4).The comparisons of treatment outcomes between late and non-late initiation are shown in Table 3). The percentages of overall regimen modification, regimen modification due to adverse events, and simplification were all similar when the comparisons were stratified by late cART initiation  or initiating cART at CD4 cell counts <500 cells/mm3 . Patients initiating cART late and at CD4 cell counts <500 cells/mm3 were more likely to modify cART for virological failure, with the estimated HR of 2.82  and 2.58  in univariate analysis, respectively. The negative impact of late cART initiation on virological response was observed not only in the patients initiating cART at PVL <100,000 but also those at PVL ≧100,000 copies/mL Click here for additional data file.S1 Data(XLSX)Click here for additional data file.


Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, rapidly progressive hematologic disorder involving uncontrolled immune system activation. HLH has been associated with viral infections, including human immunodeficiency virus (HIV) infections. We report a case of a critically ill 30-year-old female who was hospitalized with HIV-associated HLH, with a CD4 count of 4 cells/mL and HIV viral load of 1,842,730 copies/mL. After ruling out other potential infectious causes of HLH, antiretroviral therapy (ART) was initiated with darunavir, ritonavir, tenofovir, and emtricitabine. Within one week of initiation of ART, the patient began to improve clinically and hematologically and was stable enough for discharge from the hospital three weeks after starting therapy. This case suggests that treatment with ART in patients with HIV-associated HLH should be considered even in critically ill patients with low CD4 counts. Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, and rapidly progressive condition caused by excess activation of the immune system. HLH can be precipitated by a variety of triggers, including infection, rheumatologic diseases, or malignancy. Treatment often requires chemotherapy and corticosteroid therapy, along with treating any underlying causes of HLH. Even with standard treatments, prognosis of patients with HLH is poor with approximately 50–60% survival , 2. HereTmax of 39.9C, heart rate of 122 beats per minute, respiratory rate of 30 breaths per minute, and blood pressure of 91/57 mmHg, saturating at 97% on 35% FiO2. Complete blood count revealed white blood cells of 3 × 103 cells/mL with 73% segs and 15% bands, hemoglobin of 4.5 g/dL, hematocrit of 17.7%, and platelets of 4,000 cells/mL. Ferritin was significantly elevated at 19,406 ng/mL and triglycerides were 412 mg/dL. HIV viral load was 1,842,730 copies/mL and CD4 count was 4 cells/mL. Physical exam revealed hepatosplenomegaly which was confirmed by abdominal ultrasound. The patient was diagnosed with HLH based on meeting the required five of eight criteria set forth in HLH-2004 guidelines  [A 30-year-old Caucasian female presented to the emergency department with complaints of increasing lethargy and fatigue over the course of several weeks, along with a one-day history of shortness of breath, hematemesis, and palpitations. Past medical history was significant for HIV, anemia, and septoplasty. She was intubated on admission for airway protection due to concern for impending respiratory failure. On exam she was found to be febrile with  Pneumocystis jirovecii, acid fast bacilli, cytomegalovirus, parvovirus, Epstein-Barr virus, cryptococcus, histoplasmosis, syphilis, and influenza A. The only positive finding was antibody for influenza B, which was attributed to a mild upper respiratory infection that had resolved on its own with supportive measures two weeks prior to admission.The patient was placed on empirical antibiotics (levofloxacin and vancomycin) for sepsis while investigation for infectious source was conducted. She was also started on methylprednisolone for respiratory failure at admission, which was continued for three days. Blood and urine cultures were negative. Sputum culture grew normal flora. Tests were negative forDespite aggressive transfusions, significant anemia and thrombocytopenia persisted. At this point, the most likely trigger of the HLH was determined to be an uncontrolled HIV infection. Given the patient's clinical instability and unresponsiveness to supportive treatment, ART was empirically initiated with tenofovir/emtricitabine, darunavir, and ritonavir. Within one week of initiation of ART, the patient improved clinically and was able to be extubated, and her laboratory parameters began to normalize . By the HLH has been associated with viral infections, including Epstein-Barr virus, cytomegalovirus, herpes simplex virus, influenza, and human immunodeficiency virus (HIV) –6. HLH hSeveral reports have been published describing patients with HIV-associated HLH who have been successfully treated with ART, with reports of clinical response occurring within five to seven days of initiation of ART. These patients, however, all had CD4 counts that were much higher than our case patient. One case of HIV-associated HLH in a 27-year-old male with a CD4 count of 138 cells/mL was treated with zidovudine, lamivudine, lopinavir, and ritonavir with clinical improvement seen within five days . A thirdDespite the efficacy of ART treatment in HIV-associated HLH, some case reports have shown that initiation of ART may be ineffective in some patients. A 32-year-old male with HIV-associated HLH with a CD4 count of 100 cells/mL was treated with efavirenz, lamivudine, and tenofovir without clinical improvement after three weeks of ART treatment; clinical improvement was seen within 24 hours of splenectomy . AdditioIn our patient with HIV-associated HLH, despite a very low CD4 count of 4 cells/mL, initiation of ART was not associated with IRIS or other adverse outcomes. Clinical improvement was seen within one week of treatment initiation with ART consisting of darunavir, ritonavir, tenofovir, and emtricitabine. The individual antiretroviral drugs composing the ART regimen are not suspected to be responsible for the clinical improvement of patients with HIV-associated HLH; rather, the initiation of ART to treat the underlying HIV infection is likely responsible. There is currently not enough information to determine if one ART regimen is better than another regimen in the treatment of HIV-associated HLH.The time to clinical improvement in this patient is consistent with previously reported times to clinical improvement in patients with HIV-associated HLH treated with ART. Prompt treatment with ART has been previously suggested as an effective treatment strategy in patients with HIV-associated HLH , 10. The