HIV-associated neurocognitive disorder (HAND) is a consequence of HIV infection of the central nervous system. The prevalence ranges between 15% and 60% in different settings.This prospective study determined the prevalence of HAND at a peri-urban HIV clinic in KwaZulu-Natal. Factors associated with HAND were examined, alternate neurocognitive tools were tested against the international HIV dementia scale (IHDS) score and an association between HAND and non-adherence to antiretroviral therapy (ART) was explored.Between May 2014 and May 2015, 146 ART-naïve outpatients were assessed for HAND. IHDS score ≤ 10 established a diagnosis of HAND. Functional capacity was assessed using Eastern Cooperative Oncology Group (ECOG) score. Chi-squared test was used to identify risk factors for HAND. The get-up-and-go test (GUGT) and Center for Epidemiological Studies Depression scale – revised (CESD-r) were tested against the IHDS. HIV viral load done six months after initiating ART was used as a surrogate marker for adherence to ART.p = 0.003). There was no correlation between the GUGT, CESD-r and the IHDS score. HAND was not associated with non-adherence (p = 0.06).The prevalence of HAND was 53%. In total, 99.9% of patients with HAND had no functional impairment. Age > 50 years old was associated with HAND (While the prevalence of HAND is high, it is not associated with functional impairment which suggests that asymptomatic neurocognitive impairment is prevalent. Age > 50 years old is a risk factor for HAND. The GUGT and CESD-r are not useful diagnostic tools for HAND. The relationship between HAND and non-adherence should be further explored. HAND has not been studied in KwaZulu-Natal where the prevalence of HIV approaches 40% according to the South African 2013 national antenatal sentinel HIV prevalence survey.The introduction of combination antiretroviral therapy (cART) has led to a decrease in the prevalence of HAND, which ranges between 15% and 60% in different settings.15 These are time-consuming and require expertise from skilled personnel making them impractical for a busy HIV clinic in resource-limited settings.16 Furthermore, they often require a patient to have received a formal education which may be a limiting factor in developing countries. The international HIV dementia scale (IHDS), a simple and pragmatic assessment tool developed in the United States of America (USA), showed a sensitivity of 80% and specificity of 55% when tested against standardised neurological and neuropsychological assessments in the USA and Uganda.18 The validity of the IHDS was tested in a South African healthcare facility and showed a sensitivity of 45% and a specificity of 79%.20A range of clinical tests have been used to assess the neurocognitive function of HIV-infected patients.21 An earlier study conducted in Los Angeles found an association between HAND and non-adherence but only in patients more than 50 years old.22 The link between HAND and adherence remains a largely controversial subject with conflicting evidence.25Kelly et al. studied the association between HAND and adherence to ART in a Malawian adult population. ART adherence was assessed using serum ART drug levels. The study found that HAND was not associated with non-adherence.The objectives of this study were to determine the prevalence of HAND, and the functional capacity of those with HAND, in a peri-urban ART clinic in KwaZulu-Natal, South Africa. Factors associated with HAND were studied, and the association between HAND and non-adherence to ART was explored. The utility of two other clinical assessment tools, namely, the get-up-and-go test (GUGT) and Center for Epidemiological Studies Depression Scale – revised (CESD-r) were tested against the IHDS to determine whether they could be used as alternatives to the IHDS in this setting.26 greater than or equal to 80 were screened. Those who were older than 65 years old, those with poorly controlled hypertension, a past embolic or haemorrhagic stroke, past CNS opportunistic infections  and patients with a history of psychiatric illness or current mental healthcare user were excluded.The study was conducted at a regional, peri-urban HIV clinic in KwaZulu-Natal. Consecutive HIV-infected patients who were ART-naïve with a Karnofsky scoreAll patients who met the requirements and provided written informed consent were enrolled between May 2014 and May 2015.A trained research assistant administered and obtained the informed consent and performed the neurocognitive tests: IHDS, GUGT and CESD-r. Functional capacity was assessed by the Eastern Cooperative Oncology Group (ECOG) performance status. Baseline CD4 count, co-morbidities and a history of alcohol consumption were captured. The IHDS was performed on each patient. An IHDS score ≤ 10 was used to diagnose HAND. In addition, the GUGT and the CESD-R were performed. All data were captured on a case record form.Follow-up data including IHDS, GUGT and CESD-r were captured at the 6-month post-ART initiation visit in those patients who were not transferred out of the clinic and those who presented for this follow-up appointment. HIV viral load results were obtained after six months of ART as per South African Department of Health HIV guidelines. A detectable viral load after six months of ART use was used as a surrogate marker for non-adherence. Detectable viral load was defined as an HIV viral load above 20 copies/mL or 50 copies/mL depending on the assay used.®. Descriptive data were summarised as mean, median and proportions. Chi-squared test was used to examine factors potentially associated with HAND and to investigate the association between HAND and a detectable viral load. Correlations between the IHDS and GUGT and the IHDS and CESD-r were assessed using Pearson’s correlation coefficient. Statistical significance was considered at p < 0.05.Data were captured and analysed using Microsoft Excel 2010The protocol was approved by the University of KwaZulu-Natal Biomedical Research Ethics Committee (ref: BE421/13), KwaZulu-Natal Department of Health and hospital management.Between May 2014 and May 2015, 149 patients were enrolled. Three of the patients were unable to continue with the interview because of time constraints; therefore, a total of 146 patients were assessed for HAND. The baseline characteristics of the 146 patients are displayed in The prevalence of HAND using an IHDS score ≤ 10 was 53% (78/146). The median IHDS score among those with HAND was 9 (IQR 8.5–10). The distribution of IHDS scores among participants with HAND is displayed in r = -0.12) and CESD-R (r = -0.02) did not correlate with the IHDS score.Functional capacity of the patients assessed by the ECOG performance status was 0 in 99.9% of patients with HAND. The GUGT (p = 0.003). There was no association between CD4 count < 200 cells/mm³ and HAND (p = 0.14). Remarkably, alcohol use appeared to be protective (p = 0.01). Comprehensive data on alcohol use were not collected; therefore, this finding could not be explored further. Nineteen patients had a diagnosis of tuberculosis (TB) at enrolment or follow-up. This was not associated with HAND.The factors that were investigated for their association with HAND are displayed in p = 0.06). Viral load results were not available for 17 patients who were lost to follow-up.HIV viral load after six months of ART was traced in 129/146 (88%) of patients. A detectable viral load, used as a surrogate marker for non-adherence, was found in 24/69 (35%) with HAND and 12/60 (20%) without HAND. While there appeared to be a trend towards an association between a detectable HIV viral load and the HAND group, the association was not statistically significant (p = 0.02). Significant improvements in the other test scores were not found.The IHDS, GUGT and CESD-r were re-administered to 71 (48.6%) patients at the 6-month follow-up visit. The improvement on the different test scores after six months of ART use is illustrated in The 6-month follow-up CD4 count results of 59 patients were traceable. Of the 59 patients, 52 patients had an improvement in CD4 count with a mean increase of 130 cells/mm³. Although more patients in the HAND group (89% vs. 82%) had an improvement in CD4 count, this was not statistically significant.This prospective, cross-sectional, descriptive study found a high prevalence of HAND in this peri-urban population. The patients diagnosed with HAND had no functional impairment. Age over 50 years was associated with the presence of HAND. The association between HAND and non-adherence was not significant. There was no correlation between the IHDS and the CESD-r and GUGT scores.13 Most patients with HAND were asymptomatic as the functional capacity was preserved in 99.9% of patients. This suggests that ANI in this study population is the predominant manifestation of HAND which may only be diagnosed if patients are screened. ANI increases the risk of symptomatic HAND by two- to six-fold.9 It is, thus, important to make the diagnosis as early as possible. Given that the prevalence of ANI is high and that ANI is a risk factor for the development of symptomatic HAND, it is likely that the prevalence of MND and HAD are also high in those with more advanced HIV disease. Unfortunately, this was not assessed in this study.The prevalence of HAND in this community is higher than that previously described in South Africa.28 Exclusion of patients greater than 65 years of age limited the number of elderly patients studied. Inclusion of this age group may have made this variable more significant. The protective effect of alcohol use requires further exploration as insufficient information was collected to explore this further.Age greater than 50 years old was identified as a risk factor for HAND, which is in agreement with previous findings.29 HAD, in particular, has been associated with low CD4 counts. ANI was the predominant form of HAND in this population and may develop irrespective of CD4 count. As none of the patients in this study had evidence of MND or HAD, the association between CD4 count and the symptomatic forms of HAND could not be confirmed.CD4 counts at all levels were not significantly associated with the diagnosis of HAND. This finding is not in agreement with other studies.TB is highly prevalent in this setting; therefore, it is not surprising that a high proportion of patients were HIV and TB co-infected. The association between TB and HAND has not been previously described. In this study population HIV and TB co-infection was not associated with HAND.30 It was postulated that it would be a useful adjunctive test; however, correlation between IHDS and the GUGT was not found. Mood and behavioural changes may be the first symptoms experienced by patients with HAND.2 The IHDS does not assess these components. We, thus, used the CESD-r to determine levels of depression.31 This tool has been used to determine the prevalence of HAND in a Nigerian study and may be implemented by non-medical staff, which makes it an attractive option in resource-limited settings.32 Although a significant proportion of patients had a score that suggested a depressed mood, the score did not correlate with the IHDS. Therefore, the GUGT and CESD-r are not recommended for use in the diagnosis of HAND in this setting.Adjunctive tests were carried out to determine whether they were useful to diagnose HAND and could, in fact, replace the IHDS. The GUGT is an easy-to-implement test used to evaluate elderly patients with dementia.25 A detectable viral load taken six months after ART initiation was used as a surrogate marker for non-adherence to ART.33 A statistically significant association between HAND and a detectable viral load was not found in this study.25 A larger, more in-depth study may be necessary to explore this association fully. If a conclusive link between HAND and non-adherence is found, it may necessitate a change in ART clinic follow-up and counselling algorithms for patients diagnosed with HAND.We hypothesised that there would be an association between HAND and non-adherence to ART. Current literature provides conflicting data.10 In this study, there was a statistically significant improvement in IHDS scores in those with HAND after six months of ART use. HAND is not routinely screened for in South African HIV clinics at present; therefore, a diagnosis of ANI may often be missed. However, as the ART programme expands in South Africa, and more patients are commenced on ART earlier in the course of the infection, it is likely that the prevalence of HAND will decrease in keeping with trends in other countries.35Widespread use of ART has resulted in a significant reduction in the prevalence of HAND.Currently, HAD, the most severe form of HAND, is the only neurocognitive ART eligibility criterion included in the World Health Organization (WHO) clinical staging of HIV and AIDS. South Africa has adopted the ‘ART for all’ guidelines; however, in other developing nations where access to ART is limited, a diagnosis of HAND (symptomatic and asymptomatic) should be an indication for ART initiation. Given the deleterious neurocognitive consequences of untreated ANI, screening is recommended so that this disorder does not go undetected.The study was limited by selection bias. Patients older than 65 years old and patients with a Karnofsky score of lower than 80 were excluded from the study, which may account for the absence of participants with symptomatic forms of HAND. The WHO clinical HIV stage of each patient was not collected, which may have provided further information on the baseline clinical condition. We were not able to follow-up all the patients who were enrolled because of loss to follow-up and referrals out of the clinic. There were missing data for patients who were lost to follow-up. Additionally, ART drug levels could not be measured to accurately determine patient adherence.This study provides important information on the prevalence of ANI in this setting where the burden of HIV is high. In addition, it demonstrates that patients with HAND (ANI in particular) may be managed using the same follow-up and counselling algorithms as those without HAND as adherence does not appear to be adversely affected by the neurocognitive impairment.The inclusion of cerebrospinal fluid HIV viral load to confirm the diagnosis of HAND may be considered for future studies although the use of invasive investigations such as a lumbar puncture for this clinical indication may be a challenge in resource-limited settings. Imaging of the brain was not possible because of cost and access; however, it may be helpful to understand the morphological changes that occur in the brain and should be considered in future studies.The prevalence of HAND in this study population is higher than previously reported in South Africa. ANI is the only form of HAND detected in this study population. Age greater than 50 years old is a risk factor for HAND. A CD4 count less than 200 cells/mm³ does not appear to be associated with ANI. This study did not find a relationship between HAND and non-adherence to ART; however, this needs to be explored further.


While efficacy data exist, there are limited data on the outcomes of patients on third-line antiretroviral therapy (ART) in sub-Saharan Africa in actual practice. Being able to identify predictors of switch to third-line ART will be essential for planning for future need. We identify predictors of switch to third-line ART among patients with significant viraemia on a protease inhibitor (PI)-based second-line ART regimen. Additionally, we describe characteristics of all patients on third-line at a large public sector HIV clinic and present their early outcomes.Retrospective analysis of adults (≥ 18 years) on a PI-based second-line ART regimen at Themba Lethu Clinic, Johannesburg, South Africa as of 01 August 2012, when third-line treatment became available in South Africa, with significant viraemia on second-line ART  to identify predictors of switch to third-line (determined by genotype resistance testing). Third-line ART was defined as a regimen containing etravirine, raltegravir or ritonavir boosted darunavir, between August 2012 and January 2016. To assess predictors of switch to third-line ART we used Cox proportional hazards regression among those with significant viraemia on second-line ART after 01 August 2012. Then among all patients on third-line ART we describe viral load suppression, defined as a viral load < 400 copies/mL, after starting third-line ART.Among 719 patients in care and on second-line ART as of August 2012 , 36 (5.0% over a median time of 54 months) switched to third-line. Time on second-line therapy (≥ 96 vs. < 96 weeks) (adjusted Hazard Ratio (aHR): 2.53 95% CI 1.03–6.22) and never reaching virologic suppression while on second-line ART (aHR: 3.37 95% CI 1.47–7.73) were identified as predictors of switch. In a separate cohort of patients on third-line ART, 78.3% (47/60) and 83.3% (35/42) of those in care and with a viral load suppressed their viral load at 6 and 12 months, respectively.Our results show that the need for third-line is low (5%), but that patients’ who switch to third-line ART have good early treatment outcomes and are able to suppress their viral load. Adherence counselling and resistance testing should be prioritized for patients that are at risk of failure, in particular those who never suppress on second-line and those who have been on PI-based regimen for extended periods.The online version of this article (10.1186/s12981-018-0196-9) contains supplementary material, which is available to authorized users. In many resource-limited settings (RLS), antiretroviral therapy (ART) treatment guidelines call for switching patients who fail non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease-inhibitor (PI) based second-line regimens , 2. EstiWhile the availability of second-line ART is expanding in RLS, only a few countries in these settings have treatment options for patients who fail both NNRTI and PI-based first and second-line therapies respectively . Yet as Since 2009 the World Health Organization (WHO) has recommended that third-line regimens be made available in all countries . Third-lSouth Africa is one of the few countries in sub-Saharan Africa that has access to both resistance testing for patients failing second-line, as well as third-line drugs such as ETV, DRV/r and RAL in the public sector. As such we sought to use data from one of the largest cohorts of patients on second-line treatment in sub-Saharan Africa that also had access to third-line. This enabled us to identify predictors of switching to third-line ART among those with significant viraemia on second-line therapy as well as describe early outcomes of patients on third-line ART.We conducted a retrospective cohort study among adults ≥ 18 years) attending Themba Lethu Clinic in Johannesburg, South Africa. The Themba Lethu Clinic cohort, which has been described in detail elsewhere , 13, is 8 years aSouth Africa uses HIV viral load testing to determine when a patient is considered to have failed an ART regimen. First-line treatment failure, defined as virologic failure, is defined as persistent viral loads ≥ 1000 copies/mL on two occasions within a 3 month interval –19. GiveThe management of patients failing second-line ART using intensified adherence counselling has been described before , 22. BriAt Themba Lethu Clinic, longitudinal clinical and demographic data are collected and stored on the electronic patient management system, TherapyEdge-HIV™. CD4 cell counts and viral load results are imported directly into the database from the National Health Laboratory Service (NHLS) each day. Death is ascertained through patient tracing and is often reported or confirmed by family. Where available (61%), patients national identification numbers are linked with the National Vital Registration System to confirm all-cause mortality/death , 24.As the study had two main objectives we analysed data from two overlapping study cohorts.To predict switch to third-line we included adult (≥ 18 years at the availability of third-line) patients who were on a PI-based second-line regimen as of 01 August 2012 at Themba Lethu Clinic. The analysis was restricted to patients with significant viraemia on second-line ART; those who had at least one viral load recorded at least 3 months after commencing second-line ART and had a viral load ≥ 1000 copies/mL on at least one occasion after the availability of third-line ART (01 August 2012) –27.® or any of the standard first-line agents used in the treatment of TB; rifampicin, isoniazid, pyrazinamide, streptomycin, ethambutol etc.) after the start of second-line ART but before 01 August 2012. Current TB treatment was defined as a TB diagnosis recorded or the prescription of anti-TB medication after the start of second-line ART and is still being administered as of 01 August 2012.Current age, second-line regimen, viral load and CD4 count are defined as the value closest to 01 August 2012. Initiating second-line regimen was defined as the first PI-based regimen after April 2004 but before 01 August 2012. Time on second-line ART, calculated from start of second-line until 01 August 2012, was categorized at 96 weeks based on standardized reporting of outcomes at 0, 24, 48 and 96 weeks. History of Tuberculosis (TB) treatment was defined as a TB diagnosis recorded in the clinical conditions or the prescription of anti-TB medication  for continuous variables.We considered the following viral load responses as potential predictors of switch to third-line ART: (i) never suppressed on second-line ; and (ii) viral load blips on second-line ART (0 vs. ≥ 1) . Additionally, we considered other potential predictors of switch to third-line ART such as regimen change, defined as any change in regimen from the patients’ initiating second-line regimen before 01 August 2012.To assess predictors of switch to third-line ART we used Cox proportional hazards regression among those with significant viraemia on second-line ART post 01 August 2012. Follow-up time was calculated from 01 August 2012 (the availability of third-line ART), until the earliest of switch to third-line, death, loss to follow-up (LTF), transfer-out or close of dataset on 19 January 2017. Loss to follow-up was defined as being ≥ 3 months late for the last scheduled visit with no subsequent visit. Variables with a p value less than 0.1 in the univariate analysis and a priori variables (e.g. age and gender) were included in the final multivariate model. Because the number with the outcome of interest was limited (n = 36), the final model was restricted by the number of independent variables that could be added (i.e. one independent variable for every five to ten outcomes observed). All analyses were conducted using SAS version 9.3 .To describe characteristics of patients on third-line ART as well as their virologic outcomes, we included all adult patients . Medical file reviews were used to confirm the start date of third-line treatment. Clinical trial patients who transferred into Themba Lethu Clinic on a regimen containing one of the third-line drugs  were excluded if available data confirmed that the clinical trial was not a third-line clinical trial .For the third-line cohort CD4 count and viral load closest to the start of third-line ART were defined as a CD4 count and viral load result after 01 August 2012, but no more than 14 days post third-line initiation to allow for laboratory reporting and capturing when manual data entry was required. We categorized third-line patients into: (1) those that had initiated third-line ART at Themba Lethu ; and (2) those that had been transferred into Themba Lethu Clinic on a third-line regimen . We also report the proportion of patients that started third-line in a clinical trial.The primary outcome for the third-line cohort was viral load suppression on third-line ART; defined as a viral load < 400 copies/mL closest to 12 months post third-line initiation (± 3 months). We also estimate the proportion of patients virally suppressed (< 400 copies/mL) at the first follow-up viral load recorded, taken > 1 month but ≤ 6 months after the start of third-line ART (early suppression). Additionally, time to first ever suppressed viral load on third-line ART was defined as the time in months from 1 month post third-line ART initiation to first ever suppressed viral load (< 400 copies/mL) recorded within the 12 (± 3) months of follow-up from third-line initiation.For the third-line cohort, we again present demographic and clinical characteristics using proportions for categorical variables and medians with corresponding IQRs for continuous variables.For patients who transferred-out to another facility after start of third-line ART, we reviewed the patient clinic file and recorded the transfer-out facility. Where possible, we traced patients (using their unique patient identification number on TherapyEdge-HIV™) to the transfer facility and recorded viral load results that were available. This allowed us to assign a viral load outcome to patients that were previously reported as transfer-out.Among 719 patients in care, on second-line ART at Themba Lethu Clinic with significant viraemia after 01 August 2012, more than two-thirds were female  with a median age of 39.4 years (IQR 33.3–46.3). Most patients initiated on a second-line regimen of TDF, 3TC/FTC and LPVr , followed by zidovudine (AZT), AZT, 3TC/FTC and LPVr  and then AZT, LPVr and didanosine (ddI)   switched to third-line ART. When looking at poor viral load response during second-line ART, a higher proportion of patients who switched to third-line (n = 36) experienced viral load blips on second-line ART (46.7% vs. 34.3%) or never suppressed on second-line ART (27.3% vs. 14.4%).While no differences were observed across gender, age groups and regimen change, we found that time on second-line prior to the availability of third-line ART, calculated from start of second-line until 01 August 2012, was a strong predictor of switch among those with significant viraemia . When considering indicators of poor viral load response patients who never managed to suppress their viral load while on second-line therapy were more likely to switch to third-line ART (aHR 3.37 95% CI 1.47–7.73) (Table Table 3 (IQR 194.0–439.0) and median viral load was 13,930.0 copies/mL .Of those on third-line, 37.8% were male (n = 31) and the median age at third-line initiation was 40.0 years (IQR 35.5–47.3). At third-line ART initiation, the CD4 count was 277.0 cells/mm3 (48.4 vs. 25.9%), lower median viral load  around the first recorded date of third-line ART as well as year starting third-line ART . Of the 46 patients identified to be referrals to third-line therapy (i.e. transferred into Themba Lethu Clinic on third-line), 10 (21.7%) had initiated treatment in a clinical trial  were similar to those that initiated second-line ART and switched to third-line ART at Themba Lethu Clinic in terms of the characteristics described in Table 6 were siAt the end of follow-up the majority of patients were alive, in care  while 6.1% had transferred out (n = 5/82), 1.2% were loss to follow-up (n = 1/82) and 4.9% had died (n = 4/82)  were virally suppressed (n = 16/36) by 12 months after third-line ART initiation. This was higher than the 41.3% (95% CI 27.8–55.9%) suppression among referral patients (n = 19/46).As ART programmes in sub-Saharan Africa mature, increasing numbers of people will require third-line regimens. Here we report that 5% of patients with significant viraemia on second-line ART at Themba Lethu Clinic switched to third-line ART (over a median time of 54 months). The small proportion in need of third-line is consistent with what has been previously reported .Implementation of third-line ART is resource intensive and requires more expensive drugs, access to resistance testing and an individualized approach to therapy where drug history, treatment toxicities and resistance patterns of patients are all taken into account. In a recent study of 400 patients with significant viraemia on second-line  at Themba Lethu, the majority (65%) were able to re-suppress their viral load within 6 months following an adherence intervention while only 6% required third-line ART , 28. StuA high HIV RNA at baseline or start of second-line ART has been demonstrated by others as a strong independent predictor of second-line failure –33. In aStudies have demonstrated that patients who have suboptimal adherence to first-line ART are more likely to have suboptimal adherence to second-line ART and probably also third-line ART . Therefo3; 15.4% vs. 7.8%). Others have also shown that lower CD4 count at start of second-line predicts failure to achieve viral suppression on second-line ART [Compared to those who remained on second-line and did not switch, we show that patients who switched to third-line had lower CD4 counts at the start of follow-up (01 August 2012)  suppressed their viral load on third-line ART by 12 months . More specifically, majority of third-line patients  achieved viral suppression in the first 6 months (early suppression). Time to first ever suppressed viral load while on third-line was relatively short with two-thirds of patients achieving their first ever suppressed viral load within 6 months of third-line initiation (59.8%). These results are consistent with those reported from Mumbai, India where most  patients achieved virologic suppression after a median duration of 6 months (183 days) on third-line ART . VirologModerate to high rates of loss to follow up (1.2%) and transfer-out (6.1%) respectively, may have restricted repeat viral load testing and subsequently underestimated suppression rates. To overcome this we managed to trace and obtain viral load outcomes for four of the five transfer-out patients. All four patients with viral load results were suppressed. For those patients with viral load data between 1 and 12 months of starting third-line (n = 71), 8.5%  never suppressed their viral load below 400 copies/mL.This study has several limitations in addition to those already mentioned. We included patients on second-line ART as of 01 August 2012, when third-line became available, which may have introduced selection bias. Some potential predictors of treatment failure such as measures of adherence and routine resistance testing were not assessed in this study. However, the examination of more proximal determinants of significant viraemia (duration of current therapy and virologic response) may be important to evaluate, particularly in resource-limited settings where robust measures may not be readily available. Additionally, after March 2012 the standard of care for patients with an elevated viral load while on second-line therapy has improved with more intensified adherence counselling, follow-up and more frequent visits with experienced medical officers . Our resOur results show that the need for third-line, based on significant viraemia while on second-line ART, is low (5% over a median time of 54 months). But that patients’ who switch to third-line ART have good early treatment outcomes and are able to suppress their viral load. Adherence counselling and resistance testing should be prioritized for patients that are at risk of failure, in particular those who never suppress on second-line and those who have been on PI-based regimen for extended periods. Despite a poor response to second-line ART, we report 57.3% (47/82) of all patients on third-line ART suppressed their viral load during the first 6 months on third-line therapy. In addition, tracing initiatives confirmed that 93.9% (77/82) of patients on third-line remained alive and in care by 12 months.Additional file 1: Table S1. Summary of third-line patients transferred in from clinical trials (n=10).


Treatment failure (TF) and adverse drug reactions (ADRs) are the main indications for antiretroviral therapy (ART) regimen change. Identification of factors influencing regimen change and subsequent health outcomes of patients after regimen change is essential in providing a sustainable and effective antiretroviral roll-out campaign.To confirm the factors that influence antiretroviral regimen change and to evaluate patient outcomes post regimen change.A retrospective chart analysis of 269 HIV-infected non-pregnant patients (age >18 years), who underwent an antiretroviral (ARV) regimen change and were followed up for approximately one year since initiation, was undertaken at a Provincial Hospital ARV Clinic in KwaZulu-Natal, from January 2008 to December 2012.n = 111(41%). The most common regimen patients were changed to was tenofovir (TDF)/3TC/EFV n = 89(33%). Stavudine was the most commonly substituted drug (35.5%). Lipodystrophy was the most common ADR (56.8%). ADR was the indication for ART regimen change in 175 patients (65%), whilst TF accounted for ART regimen change in 94 patients (35%). Immunological success (CD4 counts) was shown after regimen change . Undetectable viral loads were measured in 172/205 (83.9%) patients post regimen change.Of the 269 patients, there were 200 females (75%). Most patients were between the ages 30 and 44 (57.6%). Only five patients had coexisting tuberculosis (TB) infection (2%). The most common first-line ART regimen to be changed was stavudine (D4T)/lamivudine(3TC)/ efavirenz(EFV) ADRs were the main cause for antiretroviral regimen change. Stavudine was the most substituted drug with lipodystrophy being the most common side effect. Coexisting TB infection did not influence regimen change. Immunological and virological success was shown after regimen modification. In April 2010, treatment was offered in fewer than 500 facilities – by the end of 2013 that number had risen to over 3500, and the number of people receiving antiretroviral therapy (ART), from less than 1 million to greater than 2 million.1South Africa has the highest number of HIV-infected people worldwide with an estimated 5.6 million people living with HIV.2 These two factors are intimately related as an ADR may lead to poor adherence, which ultimately results in TF.2 During the period 2007–2011, drug-related toxicity from first-line regimens was found to be a major contributing factor to ART regimen change in the South African context.3 ART regimen change can be challenging when drug availability, cost and acceptable combinations are limited by their pharmacokinetic and toxicity profiles, thus allowing for only a certain number and class of drug substitutions to occur. Personal determinants of poor adherence have been investigated, which included factors, such as stigma, discrimination, depression and alcohol, that would negatively affect patients’ outcomes.2Despite the success in access and distribution of ART, several challenges exist with respect to adverse drug reactions (ADRs) and treatment failure (TF), which are indications for ART regimen change.4 Despite the reported success, several drug interactions exist between ART and anti-TB therapy consequently affecting the pharmacokinetic properties of ART, often resulting in reduced plasma levels of both non-nucleoside reverse transcriptase inhibitors and protease inhibitors (PI).5 This may contribute to TF, thus influencing ART regimen change.The resurgence of tuberculosis (TB) has largely paralleled the HIV pandemic with more than 50% of HIV-infected patients developing TB in their lifetime. Highly active antiretroviral therapy (HAART) has led to a decrease in HIV-associated TB by more than 80%.6Frequent monitoring enables the diagnosis of virological failure before the development of drug resistance mutations, which would ultimately lead to TF and allow for possible viral transmission.Monitoring the immunological (CD4) and virological response  to ART regimen change is essential in determining the efficacy of regimen changes and individual drug substitutions.Hence, the aim of this study was to confirm and quantify the factors that influence ART regimen change and to evaluate the health outcomes of the patients post regimen change using CD4 and VL as markers.A retrospective chart analysis of 269 HIV-infected patients who underwent an ART regimen change between January 2008 and December 2012 and who were followed up for approximately one year after an ART regimen change at a rural Provincial Hospital ARV Clinic, situated in Newcastle, KwaZulu-Natal, South Africa, was undertaken. Patients who had a regimen change were sampled in chronological order. Data were manually retrieved from outpatient files.Patients under 18 years of age and pregnant patients were excluded from the data analysis, the latter being excluded because the Madadeni Hospital ARV Clinic does not render a maternity and paediatric service. Variables included in the data analysis were age, gender, first-line ART regimen, coexisting TB infection, modified ART regimen, ADRs, drug substitutions, indication for regimen change and time to regimen change.Outcome measures included the viral load and CD4 counts prior to ART regimen change and at six months follow up after ART regimen change. An undetectable viral load was given a numerical value of 39 for purposes of statistical analysis.t-test was used to compare continuous variables. A p < 0.05 was considered statistically significant. SPSS version 23 software  was used for the data analysis.Descriptive statistics, using means and standard deviations for continuous variables, and frequencies for categorical variables, were used to report sample characteristics. A Student’s Gatekeepers permission was given by the KwaZulu-Natal Department of Health Research and Development Committee with the study given full ethical approval from the Biomedical Research Ethics Committee of the University of KwaZulu-Natal (BREC No: 206/15).Of the 269 patients who underwent ART regimen change, there were 200 females (75%) and 69 males (25%). Most patients were between the ages 30 and 44 (57%); >45 years (25%) and 18–29 years (16%). Only five patients had coexisting TB infection (2%) .n = 111(41%), D4T/3TC/ nevirapine (NVP) n = 100(37%) and TDF/3TC/EFV n = 26(10%).The most common first-line ART regimens to be changed were stavudine (D4T)/lamivudine (3TC)/ efavirenz (EFV) n = 89(33%), TDF/3TC/NVP n = 75(28%) and TDF/NVP/LPV n = 55(20%) (n = 144(35.5%), EFV n = 34(12.6%) and NVP n = 34(12.6%).The most common regimens that patients changed to included TDF/3TC/EFV  55(20%)  and 3. TThe most common ADR was lipodystrophy (56.8%) .ADR was the indication for ART regimen change in 175 patients (65%) and TF reason for change in 94 patients (35%).p < 0.002. The mean follow up time for CD4 and viral load counts was 14.31 months.There was a significant difference in the time to regimen change in the TF and ADR groups (30.77 vs. 36.72 months), p < 0.001. There was a significant difference between the CD4 counts post regimen change in the TF and ADR groups (290.65 ± 180.60 vs. 543.90 ± 233.56 cells/mL), p < 0.001) (There was a significant increase in the mean CD4 counts post regimen change in the entire cohort (374.21 ± 243.16 [pre] vs. 456.09 ± 250.07 [post]), < 0.001) .Pre-ART regimen change viral load data are shown in 3 In this study, ADR (65%) was the most frequent indication for ART regimen change. The high frequency of ADR in this study may be attributed to the high number of first-line regimens containing stavudine, which accounted for the highest number of drug-specific toxicity, namely lipodystrophy. This finding is consistent with a study done by Lima et al. who have shown that 88.5% of ART regimen changes were because of ADR requiring drug substitutions.7 In another study, Kumarasamy et al. have demonstrated that the most common reason for changing ART regimens was ADR (64%),8 whereas Sidavasan et al. have shown drug toxicity to account for 27% of their ART regimen changes.9 Locally, Orell et al. have shown that only 1.7% of patients changed to a second-line regimen because of drug toxicity,10 but this study was conducted between 2002 and 2005 at which time second-line regimens were not routinely available in South Africa. Isolated drug substitutions were more commonly practised at the time.The main indication for ART regimen change globally includes TF and ADR.11 Locally, Dube et al. had shown that TF was the second most common reason for regimen change.3TF accounted for 35% of ART regimen change in this study. The low prevalence of TF may be as a result of improved levels of patient adherence because of robust counselling and patient education. Reasons cited in studies for virological failure include poor adherence, genetic factors and drug interactions, which lead to reduced antiretroviral (ARV) concentrations and transmitted drug resistance.TF has far more serious implications when switching to a second-line regimen because of the inclusion of PI. The major pitfalls of a change to a second-line PI-based regimen include complex and frequent dosing, which may lead to poor adherence.p < 0.001) and increase in CD4 lymphocyte count (p < 0.006). Virologic failure was documented in 22% of patients with adherence of 95% or greater, 61% of those with 80–95% adherence, and 80% of those with less than 80% adherence.12A study conducted by Paterson et al. of patients on PI-based regimens showed that adherence was significantly associated with successful virologic outcome  of the 183 patients for whom data on therapy were available. Adverse events led to cessation or interruption of either their TB or HIV therapy in 63 (34%) of the 183 patients. The most common side effects noted were peripheral neuropathy, rash, gastrointestinal, hepatitis and neurological events.9 Sixteen (27%) of 56 patients who received isoniazid and stavudine concomitantly developed peripheral neuropathy compared with 21 of 124 (17%) patients prescribed isoniazid without stavudine.13 In our study, the low prevalence of TB co-infection and the use of concomitant anti-TB therapy did not impact on drug–drug interactions with stavudine, which was the most common agent used in the entire cohort.Dean et al. also showed that peripheral neuropathy was the most frequently documented adverse event (21%). Twenty-two of these 39 patients (56%) were taking ARV concomitantly. This adverse event led to an interruption of TB/HIV therapy in 19 cases.13 The study stated an observed rate that was higher than that reported in HIV-infected patients without TB who were prescribed stavudine and didanosine (8%) and HIV-negative patients prescribed isoniazid for TB (0.15%). However, other studies reported a greatly increased incidence of peripheral neuropathy (55%) for HIV-infected patients prescribed isoniazid and stavudine concomitantly.13There are various reasons why patients may develop peripheral neuropathy ; the study by Dean et al. indicated that this side effect was mainly observed in patients prescribed isoniazid with antiretrovirals known to be neurotoxic.13Although the study by Dean et al. showed that a higher percentage of patients receiving this combination developed peripheral neuropathy compared with patients receiving isoniazid alone, this did not attain statistical significance. Given that a high proportion of these patients had either their TB or HIV medication changed in an attempt to alleviate the symptoms, caution should be exercised when prescribing multiple agents known to cause nerve damage in high-risk patients.13Despite the low incidence of reported ART–anti-TB therapy drug interactions in this study, clinicians should still be aware of the potential for toxicity and clinically monitor for side effects.9ADRs were most commonly caused by stavudine (D4T) (35.5%) with associated lipodystrophy being the most common side effect in this study. Other studies have shown stavudine toxicity accounted for 76% of ART regimen changes.3A local study by Dube et al. has established that 34% of patients had changed from their initial ARV regimen. This study revealed that of the patients who had changed regimen because of ARV-related toxicity, 76.1% of patients changed from a stavudine-based regimen to a zidovudine-based regimen.3In addition, the study by Dube et al. depicted that the most common adverse effects experienced by patients were polyneuropathy (24%), lipodystrophy (23.9%), neuropathy (10%) and suspected lactic acidosis (3.8%).7 The significant toxicity associated with D4T and especially after cumulative exposure has led to the removal of D4T as part of first-line ARV treatment according to the National Department of Health (NDOH) guidelines as of 2015.14 A fixed dose combination (FDC) of TDF/FTC/EFV has been implemented as part of first-line treatment since 2013. The benefits of phasing out of D4T include the exclusion of a significantly toxic drug, a reduction in stigma associated with lipodystrophy and lipoatrophy, and a decline in mortality because of lactic acidosis.14 Our findings have shown that 99% of patients were changed to a non-D4T-containing regimen in keeping with NDOH guidelines.However, Lima et al. have shown that zidovudine (AZT) was the highest substituted drug (42.4%) with anaemia as the most common adverse side effect.The inability of patients to manage the side effects associated with ARVs may result in poor adherence of treatment regimens. Management of HIV is a multidisciplinary approach. It is imperative to screen patients for signs and symptoms of adverse effects or drug toxicity. Pharmacists play a key role in ensuring the safe, rational and appropriate use of medicine, as well as provision of pharmaceutical care by monitoring patient outcomes.The mean time to ART regimen change was 34.5 months with a significantly higher duration in the ADR group. This may be attributed to the high frequency of lipodystrophy in this study population, which fares as a tolerable side effect thus delaying the urgency for ART regimen change.3 Sivadasan et al. have shown that serious drug toxicities (skin reactions) occur as early as from 2 weeks up to 42 weeks (lactic acidosis) necessitating earlier ART regimen change.9Although Dube et al. have indicated that the average time to regimen change was 14.9 months,The outcome of ART regimen change to a second-line regimen can be monitored clinically , immunologically (CD4 counts) and virologically . We chose to monitor the VL and CD4 at 6 months post regimen change to assess the therapeutic outcome. In this study, the mean follow up CD4 and VL counts were done at 14.31 months. The significant delay may be attributed to poor socio-economic status and lack of transport infrastructure especially in the rural setting.15 Another study had shown a treatment success rate of 82% following a change to a second-line regimen at 1 year follow up.16 In our study, the mean gain in CD4 count post regimen change at 14.31 months was 82 cells/mm3, which compares favourably with local studies from Johannesburg that reported a mean increase in CD4 count of 133 cell/mm3 following regimen change.17 Because of poor laboratory support and follow up, viral loads were not routinely measured in 64/269 patients (24%). In a study from Khayelitsha, South Africa, Boulle et al. have shown that viral load monitoring is an essential tool in the early identification of TF and for monitoring patient adherence even in the resource constrained setting.18There was a statistically significant increase in the CD4 count following regimen change, suggesting immunological success in both TF and ADR groups. The significant increase in the post regimen change CD4 count in the ADR group may be attributed to poor patient adherence when experiencing intolerable side effects. Virological success was achieved in 83.9% of patients who had undetectable viral load after changing regimen. The WHO has proposed that 70% of patients should achieve virological suppression (<400 copies/mL) after 6 months of ART.6 In the absence of virological monitoring, immunological monitoring by CD4 count change is recommended. However, CD4 testing has a poor accuracy and low positive predictive value for diagnosing TF. The limitations associated with immunological monitoring could lead to patients being diagnosed very late or misdiagnosed completely, with the result that patients can be kept on a failing regimen or switched unnecessarily; hence, routine virological monitoring remains the gold standard.6Frequent monitoring enables the diagnosis of virological failure before the development of drug resistance mutations, which would ultimately lead to TF and allow for possible viral transmission.Incomplete sets of data, particularly the lack of viral load data in the entire cohort, precluded an accurate assessment of virological response rates following ART regimen change. The rural-based site of the study may not be a representative of the HIV-infected patient population at large, where poor socio-economic status delays to hospital care and poor follow up of CD4 and VL are more prevalent.This study has confirmed that both ADR and TF are in fact reasons for ART regimen change in patients attending this rural ARV Clinic with ADR being a more common reason for change than TF. The most commonly implicated drug was stavudine (D4T) with its associated toxicity, namely lipodystrophy being the most common side effect. TB was not a determining factor influencing ART regimen change. The change of regimen had resulted in significant improvements in both post ART regimen immunological and virological success rates. This highlights the importance of stringent patient follow up, early identification of ADR and timeous switching to an alternative regimen.Readily available access to ARV clinics, routine monitoring of patients and appropriate patient counselling constitute key elements in ensuring favourable patient outcomes.


There are approximately 35 million people infected by human immunodeficiency virus (HIV), with an estimated 2 million incident infections annually across the globe. While HIV infection was initially associated with high rates of morbidity and mortality, advances in therapy have transformed it into a chronic and manageable disease. In addition, there is very strong evidence that those on antiretroviral therapy are much less likely to transmit infection to their partners. The success rates for maintaining viral suppression in treated patients has dramatically increased owing to the development of agents that are potent and well tolerated and can often be co-formulated into single pills for simplification. This review will outline advances in treatment over the last several years as well as new strategies that may shift the existing treatment paradigm in the near future. The development of potent antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) infection has been one of the greatest advances in modern medicine. While therapy has become increasingly easy to take and well tolerated, there remain limitations that prevent some patients from benefiting from treatment. Future goals of therapy are to overcome the limitations of current treatment, including side effects and the need to take medication on a daily basis.Early versions of potent ART that were able to suppress HIV to undetectable levels consist of regimens that included two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a protease inhibitor (PI) or a non-NRTI (NNRTI), often requiring relatively frequent dosing, had substantial side effects, frequent drug-drug and drug-food interactions, and at times were associated with a high risk of virologic failure and emergent drug-resistant virus. The next few decades of drug development focused on overcoming these limitations of treatment. Initial success included the use of pharmacologically boosted PIs that were easier to take, had fewer drug-food interactions, and were rarely associated with the emergence of drug-resistant virus. In addition, dosing frequency was simplified, ultimately to once-daily regimens. Simultaneously, there was the emergence of new NRTIs that were given as fixed-dose combinations once daily and associated with less toxicity. The next major advance in treatment was the development of a new class of therapy, integrase strand transfer inhibitors (INSTIs). Overriding all of these advances was the emergence of increasing numbers of fixed-dose combinations, including regimens that could be given as a single pill once per day. This review will summarize the advances in the last several years that have revolutionized ART along with new drugs and novel treatment strategies on the horizon.2. This is largely because of improvements in treatment options as well as data showing that treated individuals are at very low risk of transmitting to partners and progressing to AIDS and non-AIDS-related events4.The evolution of new antiretroviral agents resulted in the availability of the first truly potent regimens in 1996 that were able to suppress plasma HIV RNA to undetectable levels and prevent the emergence of drug-resistant virus. Early regimens included two NRTIs with either non-pharmacologically boosted PIs or NNRTIs. While these regimens saved lives, they were difficult to take, had numerous side effects, and, when failure occurred, were often associated with the emergence of drug-resistant virus. These limitations of therapy resulted in most guidelines suggesting that treatment should be deferred until patients were at high risk for the development of acquired immunodeficiency syndrome (AIDS)-associated complications, such as when CD4 cell counts were less than 200 cells/µL. Fast forward over the ensuing 10 years and drug development focused on agents which were easier to take, less likely to be associated with treatment failure, and often active against viruses that had underlying drug resistance. This included the recognition that pharmacologically boosted PIs could be given less frequently and were rarely associated with the emergence of drug-resistant virus, a novel observation that represented a major advance in treatment. Nevertheless, there remained substantial side effects and the need for multiple pills, and the pharmacologic-boosting agents were associated with many drug-drug interactions. These early advances did make therapy more palatable and allowed for the consideration of earlier initiation of treatment. In fact, therapy is now recommended for all HIV-infected individuals regardless of stage of disease5, and TDF is related to nephrotoxicity and more rapid declines in bone mineral density than is seen with other drugs7. In addition, the NRTIs were always combined with a “third” drug, usually a pharmacologically boosted PI, NNRTI, or more recently an INSTI, the newest class of antiretrovirals. In fact, treatment guidelines since the introduction of potent ART more than 20 years ago have continued to recommend regimens that include two NRTIs plus a third drug as preferred options2. In light of the many excellent treatment options, therapy is individualized based upon patient preference and the presence or absence of transmitted resistance and comorbid conditions, such as renal, bone, and cardiovascular problems as well as co-infections such as viral hepatitis and tuberculosis. Finally, although data are limited, ongoing research is attempting to better characterize how different treatments might impact the elevated levels of systemic inflammation and immune activation seen in virologically suppressed individuals that might adversely affect clinical outcomes9.If we now advance to the last several years, the field is marked by the emergence of NRTIs that can be given as fixed-dose combinations with far less toxicity than earlier agents in the class. In particular, this represented a move away from zidovudine, didanosine, and stavudine to abacavir (ABC) and tenofovir disoproxil fumarate (TDF). The latter drugs were co-formulated as once-daily regimens with lamivudine (3TC) and emtricitabine (FTC), respectively. While the availability of these agents represented major advances, including TDF/FTC being co-formulated with the NNRTI efavirenz (EFV) for the first single-tablet regimen, they were not without limitations. ABC has been associated in some studies with increased risk of cardiovascular eventsIn considering the advances over the last several years and on the horizon, it is worth focusing on those related to emerging NRTIs, “third” drugs combined with NRTIs, and the possibility of treating people with regimens that do not include the traditional two NRTIs plus a third drug.5. The relationship between TDF and renal disease and declining bone mineral density was similarly problematic for those with underlying renal disease or other comorbid conditions, such as diabetes mellitus, hypertension, and osteopenia/osteoporosis7. In fact, as patients living with HIV get older, clinicians are frequently encountering those with multiple comorbid conditions including underlying renal disease and cardiovascular risk factors. A challenge in this setting was how to select between NRTI-based regimens. In this setting, clinicians either made the best decision possible with close monitoring or needed to consider new options which included regimens that did not include ABC or TDF, or more recently the use of an alternative formulation of tenofovir, tenofovir alafenamide (TAF).For the majority of patients, there have been few problems associated with regimens including ABC/3TC or TDF/FTC. Nevertheless, the observations in select studies that the use of ABC was associated with increased risk of cardiovascular events, especially in those with multiple other cardiovascular risk factors, did pose some concerns for select patients2 and the Department of Health and Human Services guidelines considering it an equivalent option to TDF1. A few important caveats are noted with regard to TAF, including that the data in people with advanced renal disease, i.e. estimated creatinine clearance <50 mL/minute, are limited. In addition, TAF cannot be used with rifamycins, there are limited data and therefore it is not yet recommended in pregnancy, and there are no data using it for pre-exposure prophylaxis and therefore it is not an option in this setting. Although there are some new NRTIs in early stages of clinical development, the next big step for this class of drugs is the emergence of treatment strategies that may not include them at all, or at least not ABC, TDF, or TAF.The development of TAF, along with the approval of multiple co-formulations that include this as an alternative to TDF, represents an important advance in treatment  and darunavir (DRV) boosted by either ritonavir (RTV) or COBI are the best-tolerated options with high levels of efficacy. In addition, this class of drugs has long been known to have the unique property of rarely selecting for drug resistance, even in those experiencing virologic rebound. Recent data from a head-to-head comparison showed that DRV was as effective as ATV but somewhat better tolerated, mostly because of increased hyperbilirubinemia known to occur with ATV, a benign and reversible side effect of therapy11. That said, with few advantages of ATV over DRV, most guidelines have favored the latter, with a particular role in those where there are concerns regarding poor adherence or when treatment needs to be started before baseline drug-resistance testing is available1. The availability of fixed-dose combination of both PIs with COBI further simplifies these regimens in clinical practice13. The next potential big advance for this class relates to an ongoing study of a single-tablet regimen of DRV/COBI/FTC/TAF. Assuming data from phase III trials of this regimen are consistent with what has been seen in phase II studies14, this would be the first PI regimen that could be taken as a single pill per day.Treatment guidelines over the past several years have continued to focus on pharmacologically boosted PIs, NNRTIs, and more recently INSTI-based options15. In addition, it requires dosing with a reasonably sized meal and avoidance of acid-reducing agents. Another option on the horizon is doravirine, a new NNRTI that is given once-daily, has few side effects, and appears to be effective regardless of baseline CD4 cell count and plasma HIV RNA16.The role of NNRTIs as a third drug has been on the decline of late as a result of the expansion of the INSTIs into clinical practice, as described below. While EFV-based regimens had been the mainstay of treatment for many years, especially as the first drug included in a single-tablet regimen, there has been a shift away from this drug owing to well-known central nervous system side effects, and the development of multiple other better-tolerated drugs, including INSTIs. RPV is another NNRTI that is listed as a viable treatment option and comes as part of a single-tablet regimen with FTC and either TDF or TAF. This drug is well tolerated and effective, although potentially less so in those with plasma HIV RNA >100,000 copies/mL and CD4 cell counts <200 cells/µL17. A limitation has been the need for twice-daily dosing; however, a new formulation has been developed and shown to be as effective and as well tolerated as currently approved twice-daily dosing but will be given as two pills once per day18. The second drug in this class was EVG, which needs to be pharmacologically boosted and is part of EVG/COBI/FTC/TDF and the same three drugs with TAF that has more recently been approved. This regimen has been thoroughly studied and shown to be highly effective with good tolerability20. It is associated with drug-drug interactions and, like RAL, the emergence of INSTI resistance in the select few patients who experience virologic failure. Moreover, there is cross-resistance between these two drugs. Finally, the most recently approved INSTI is dolutegravir (DTG), which does not require boosting, is highly effective, and is generally well tolerated. A unique observation with this drug is that, in four fully-powered phase III randomized controlled trials, there has yet to be anyone who failed with resistance to any drugs in the regimen24. Based upon this, along with other data, it is believed that the barrier to resistance for this INSTI might be higher than that of other drugs in the class. It comes as a single-tablet regimen with ABC/3TC. The lack of resistance seen with this drug has raised the possibility of using it in novel combinations, several of which are discussed in the section on novel regimens below. The next potential advance in this class will be the availability of another INSTI called bictegravir that does not require pharmacologic boosting and will be combined with FTC/TAF as a single-tablet regimen. Recent phase II data show promise for safety and efficacy25, with several large randomized controlled trials underway for both first-line and switch therapy in virologically suppressed patients.The INSTIs are clearly the new darlings of ART. The first in this class was raltegravir (RAL), which has been shown to be highly effective and extremely well tolerated and has a paucity of drug-drug and drug-food interactions26. Notably, these data use a pharmacologically boosted PI no longer preferred in guidelines owing to inferior tolerability when compared with DRV and ATV. While one could likely extrapolate these data to more commonly used PIs, the data for the latter do not exist. The other large study was with DRV/RTV once-daily plus RAL twice-daily, which was overall as effective as DRV/RTV with two NRTIs27. However, in the subset of patients with plasma HIV RNA >100,000 copies/mL and CD4 cells <200 cells/µL, it was not as effective. These studies demonstrate that there are options that do not include ABC, TDF, or TAF for first-line therapy. Another potential strategy that is in advanced stages of study for first-line therapy is DTG plus 3TC. This option uses two once-daily agents and does not include tenofovir, ABC, or a pharmacologically boosted PI. A small pilot study included 20 people with screening plasma HIV RNA <100,000 copies/mL and CD4 cells >200 cells/µL and demonstrated high levels of efficacy, with 18 out of 20 patients virologically suppressed at 48 weeks28. Of the two not suppressed, one committed suicide during the study, an outcome not thought to be related to the study drug, and the other had low-level viremia that re-suppressed without a change in their regimen. A fully powered phase III study is underway with this regimen in participants with plasma HIV RNA levels of up to 500,000 copies/mL.Recent studies have attempted to deviate from the long-held paradigm of two NRTIs plus a third drug. This has largely been driven by the desire to reduce toxicity and potentially the cost of standard regimens while taking advantage of the high barrier to resistance of pharmacologically boosted PIs. In fact, there are now two large fully powered trials of first-line therapy with novel combinations that do not include tenofovir or ABC. This includes lopinavir/RTV (LPV/r) plus 3TC, which was as efficacious as LPV/r plus two NRTIs29. Notably, in these studies, those with virologic failure rarely had resistance, and when NRTIs were added to the regimen they did suppress plasma HIV RNA. There are also studies of those without any underlying drug resistance who were stable on two NRTIs plus a pharmacologically boosted PI and then followed on the PI plus 3TC alone with continued suppression30. These regimens are currently available and have mostly been used in the setting where there is a desire to get patients off tenofovir- and ABC-based regimens, such as those with progressive renal disease and risk factors for cardiovascular events or who are HLA-B5701 positive and therefore not good candidates for ABC. The need for this type of strategy has been somewhat attenuated by the availability of TAF.Other novel regimens are being pursued but for “maintenance therapy” in those already suppressed on standard therapy. There are now several large studies looking at this strategy in those with pharmacologically boosted PIs as monotherapy, which worked well but in general demonstrated a somewhat higher rate of virologic failure than did standard therapy31. The new strategy met non-inferiority criteria to the control arm and was well tolerated. In addition to being NRTI- and PI-sparing, the total mass of these pills is 75 mg, which is likely to result in a very small single-tablet regimen option.Two large phase III studies demonstrated the activity of an NRTI and PI-sparing regimen to maintain viral suppression in those without underlying resistance. Two identically designed studies called SWORD 1 and 2 randomized patients to continue their current regimen or switch to once-daily DTG plus RPV at approved doses32. This was followed by LATTE 2, which was a phase II study that initially suppressed viral load with two NRTIs plus short-acting CAB, then added short-acting RPV for 4 weeks to assure it was tolerated before stopping the drug in two groups and switching to either once-monthly or once-every-two-month intragluteal injections of nano-formulations of both RPV and CAB33. The study ultimately showed the same level of viral suppression in the two long-acting regimens compared to continued two NRTIs plus CAB, with results modestly favoring once-monthly over every-other-month dosing. Importantly, the novel regimen was well tolerated and found to be highly acceptable in those assigned to the regimen. A fully powered phase III study of monthly long-acting formulations of RPV plus CAB is now underway.One of the most exciting advances in treatment relates to the potential for long-acting regimens that would not require daily dosing. The strategy furthest along in clinical development is intramuscular nano-formulations of RPV and a new INSTI, cabotegravir (CAB). A pilot study, LATTE 1, demonstrated that short-acting RPV and CAB was effective in maintaining viral suppressionThere have been extraordinary advances in the development of ART for the treatment of HIV infection. We are now at the point where the majority of patients can be treated with a single pill per day with good tolerance and very high rates of viral suppression. New drugs in development may further expand the options available for patients. Moreover, novel regimens are in development that will allow for continued suppression with potentially fewer drugs, improved tolerability, and smaller pills without compromising efficacy. If ongoing trials are successful, we may be only a few years away from being able to offer patients treatment on a once-monthly basis.3TC, lamivudine; ABC, abacavir; AIDS, acquired immunodeficiency syndrome; ART, antiretroviral therapy; ATV, atazanavir; CAB, cabotegravir; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; HIV, human immunodeficiency virus; INSTI, integrase strand transfer inhibitor; LPV/r, lopinavir/ritonavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir.


During his interrupted human immunodeficiency virus (HIV) treatment, he was living in Mexico and incarcerated for a period of time. For the year preceding presentation with hand swelling, he was working as a cook in a Mexican restaurant in San Francisco, California, where he had frequent finger trauma from opening metal cans and preparing shrimp. Thickened flexor tendons and dactylitis were present bilaterally with stiffness and severely limited flexion and extension of his fingers  in setting of HIV treatment. Additional biopsies grew M. haemophilium from mycobacterial cultures. Treatment was changed to moxifloxacin, ethambutol, rifabutin, and azithromycin. Eight weeks later, after initial improvement, hand swelling and pain increased, accompanied by spontaneous drainage of cold abscesses on wrist, elbow, and knee, without evidence of an alternative etiology. Prednisone was administered for paradoxical IRIS for 3 months, with resolution of symptoms. After 9 months of treatment for M haemophilum, swelling and tenosynovitis fully resolved to baseline function (A 44-year-old man with acquired immune deficiency syndrome (AIDS) and CD4 fingers  and 2. H fingers , with nefunction . AntibioMycobacterium haemophilum is a slow-growing, fastidious organism that grows best at 30°C (like Mycobacterium marinum and Mycobacterium ulcerans) and requires supplementation of iron or hemin [Mycobacterium haemophilum resides in the environment and has been isolated from biofilms in fish tanks and water systems [M haemophilum have been reported in immunocompromised patients, including patients with hematologic malignancy, hematopoietic and solid organ transplantation, and HIV/AIDS. Extremity infections are the most common, namely skin and soft tissue infections, tenosynovitis, and osteomyelitis, likely related to improved growth of M haemophilum at lower temperatures [Mycobacterium haemophilum has been relatively commonly isolated among pediatric mycobacterial lymphadenitis cases when appropriate culture methods are used [Mycobacterium tuberculosis (TB). However, clinical similarities between NTM and TB-IRIS have been previously noted, and, in one series, the incidence of NTM-IRIS was 3.5% among patients initiating ART with a baseline CD4 count <100 cells/μL [M haemophilum susceptibility testing or interpretation, although there are CLSI recommendations for disk-diffusion susceptibility testing [M haemophilum is recommended with 6–24 months of a multidrug regimen that includes a macrolide, fluoroquinolone, and a rifamycin [or hemin . Mycobac systems . Infecti systems . Most caeratures , 3. Mycoare used . Dissemi


Treatment failure is a key challenge in the management of HIV-1 infection. We conducted a mixed-model survey of plasma nevirapine (NVP) concentrations (cNVP) and viral load in order to examine associations with treatment and adherence outcomes among Kenyan patients on prolonged antiretroviral therapy (ART). Blood plasma was collected at 1, 4 and 24 hours post-ART dosing from 58 subjects receiving NVP-containing ART and used to determine cNVP and viral load (VL). Median duration of treatment was 42  months, and 25 (43.1%) of the patients had virologic failure (VF). cNVP was significantly lower for VF than non- VF at 1hr  and at 4hr  but not at 24hr post-ART dosing. Up to 53.4%, 24.1% and 22.4% of the subjects had good, fair and poor adherence respectively. cNVP levels peaked and were > = 3μg.ml at 4 hours in a majority of patients with good adherence and those without VF. Using a threshold of 3μg/ml for optimal therapeutic nevirapine level, 74% (43/58), 65.5% (38/58) and 86% (50/58) of all patients had sub-therapeutic cNVP at 1, 4 and 24 hours respectively. cNVP at 4 hours was associated with adherence (p = 0.05) and virologic VF (p = 0.002) in a chi-square test. These mean cNVP levels differed significantly in non-parametric tests between adherence categories at 1hr (p = 0.005) and 4hrs (p = 0.01) and between ART regimen categories at 1hr (p = 0.004) and 4hrs (p<0.0001). Moreover, cNVP levels correlated inversely with VL (p< = 0.006) and positively with adherence behavior. In multivariate tests, increased early peak NVP (cNVP4) was independently predictive of lower VL (p = 0.002), while delayed high NVP peak (cNVP24) was consistent with increased VL (p = 0.033). These data strongly assert the need to integrate plasma concentrations of NVP and that of other ART drugs into routine ART management of HIV-1 patients. Scaling of antiretroviral treatment (ART) has significantly reduced deaths and morbidity for HIV patients. In resource-constrained settings, limited ART drug options still dampen long-term treatment success. Kenya’s standard ART regimen is still restricted to a limited combination options . At the This was a mixed method study involving both quantitative and qualitative data collection. We initially enrolled 1600 subjects across multiple study sites in Kenya into 4 interdependent sub-studies. The first 3 components of that study focused on describing the correlates of adherence and treatment outcome and genotypic variability and have been published , 28. AboAll HIV-infected adult subjects who were receiving NVP as one of the 3-drug ART regimen and returning to the clinic for refills were included on a convenience sampling basis. Fifty-five of the 58 subjects enrolled in this study component were on one of three recommended first-line treatment : nineteem2000sp platform as we described earlier. In brief, internal control RNA was added to 200μL of plasma and the sample loaded onto the m2000sp instrument for RNA extraction. The limits of detection for the m2000sp ranged between 40 and 10,000,000 HIV-1 RNA copies.VL assays were conducted withing 2 months of sample collection in duplicate. Analyses were done at the Early Infant Diagnosis Laboratory at the Kenya Medical Research Institute in Nairobi using Abbott RealTime HIV-1 assay system following manufacturer’s protocol  and using an Abbott The World Health Organization (WHO) provides three criteria for treatment failure definition that includes clinical failure, immunological failure, and virological failure . We usedWe developed an in-house liquid-liquid extraction protocol for NVP based on modification of a previous method . Frozen All patients in this study were actively receiving antiretroviral therapy (ART) at the designated clinics/facilities and their sampling was on convenience basis to include any consenting subjects meeting recruitment criteria outlined elsewhere . ChromatThis study and the consent procedure was approved by the Scientific and Ethical Review Unit (SERU) of the Kenya Medical Research Institute. Subjects 18 years or older were required to sign a written voluntary informed consent while a written voluntary informed assent of minors (<18 years) was provided on their behalf by legal guardians/parents and approved SERU.10 HIV RNA copies compared to the other regimen groups. No reason was on record for this apparent non-standard therapy. Another 53.4%, 24.1% and 39.7% had good, fair poor adherence respectively. Twenty-three (39.7%) subjects were actively involved in community peer-to-peer support (CPS) program, 17 (29.3%) only occasionally participated in CPS while 18 (31.0%) never participated in CPS. The mean baseline VL (VL1) was log10 3.33 copies, and was comparable for males (log10 3.40 copies) and females (log10 3.30 copies). To avoid any confounders to VF that might arise from suboptimal therapy, the three subjects have been excluded from statistical data analyses.There were twice as many females as males, with the overall median duration of treatment for all 58 subjects of 42 months (range 12–156). In total, 19 (32.8%) subjects received AZT+3TC+NVP, 16 (27.6%) received D4T+3TC+NVP and 20 (34.5%) received TDF+3TC+NVP regimens. Two subjects (3.4%) were on NVP+TDF and 3TC+NVP regimens and one (1.7%) on NVP alone. These 3 subjects not receiving the optimal triple ART regimen also had the highest baseline viral load (VL1) of 3.51 log10 copies) than patients on other treatment arms (p = 0.006). Defining adherence as good, fair or poor, 31 patients (53.4%) had good adherence, 14 (24.1%) had fair adherence while 13 (22.4%) had poor adherence. Adherence was strongly associated with VF outcome in a chi-square test . Subjects with good adherence also had the lowest VL (2.4log10 copies/ml) compared to those with fair (3.31 copies/ml) or poor (4.8 copies/ml) adherence. These VLs were significantly different as detailed in VF was defined using 2 successive viral load (VL) measurements as in methods. The median duration between VL1 and VL2 was 12 months for this study subset. By this definition, 25 (43.1%) of the patients failed treatment. Comparing VF outcome across ART regimen and adherence, patients receiving D4T backbone had significantly higher VL (mean VL2 4.11 log2 p<0.001). Specifically, 90.9% CPS++ patients experienced virologic success (non-VF) compared to just 22.2% of CPS- patients experiencing virologic success. Similarly, CPS++ subjects had the lowest mean VL (2.40 log 10) compared to CPS+ (3.22 log10 copies/ml) or CPS- (4.18 log10 copies/ml) subjects, and these differences were significant in an ANOVA test (p<0.001). Moreover, adherence and CPS were positively correlated in a chi-square test (p<0.001), with more patients in CPS++ showing good adherence and more CPS- patients showing poor adherence. Age and gender were not significantly associated with VF outcome.We next assessed the associations between participation in CPS and VF. A total of 22 subjects (40%) were active in CPS (CPS++), 15 (27.2%) were partly involved (CPS+) and 18 (32.7%) were never involved (CPS-). CPS activity was significantly associated with VF outcome  and fair  adherence compared to those with poor adherence  . Both cN2 p = 0.004) but not TDL1 or TDL24 was significantly associated with virologic failure. Of subjects experiencing VF, significantly more had sub-therapeutic NVP levels at the 4-hour peak  compared to just 9.4% (n = 3/32) who achieved optimal TDL yet still failing treatment. Mean VL was significantly lower for subjects who had cNVP4 at or above this threshold  compared to those with cNVP4 below the threshold . Similar analyses conducted for cNVP taken at 1hr or at 24hrs post-dosing were not significant except where otherwise mentioned. We also fitted cNVP1, cNVP4 and cNVP24 alternately into a bivariate correlation model with VL at the time of cNVP determination as the other scale variable. VL was significantly and inversely associated with cNVP1  and cNVP4 (p<0.001) but not cNVP24 in VF patients than in patients not experiencing  VF. Compp<0.001,  and withp<0.001,  but not Multivariate tests were conducted within the general linear model to assess independent associations between variables, and at least to validate the associations seen using chi square tests. Adherence and VF outcome were fitted into the step-wise model as independent variable while cNVP1, cNVP4, cNVP24, VL1 and VL2 were fitted as outcome variables. Both adherence (p = 0.004) and VF (p = 0.031) were independently and strongly associated with these outcomes . BetweenWe conducted this study to investigate associations of cNVP with treatment and adherence outcome among Kenyans receiving NVP as part of a long-term ART regimen. More than half (53.4%) of these patients had good adherence. Patients with virologic success achieved significantly high cNVP within one hour of dosing compared to delayed cNVP peak for those with virologic failure. Conversely, patients failing treatment showed poor adherence and significantly reduced cNVP. Moreover, delayed but not early peak cNVP was independently predictive of virologic failure while early peak cNVP was predictive of virologic success in multivariate analyses. We recently reported high virologic failure in a larger population of Kenyans who received HAART for between 12 and 228 months . In the NVP is extensively used in Kenya as part of first-line therapy, and VL monitoring for ART management is accessible only to a limited extent. Moreover, neither drug level nor toxicity monitoring is included in clinical management of HIV patients. The median duration between VL1 and VL2 for this study subset was 12 months, which was in line with the average duration of VL measurement intervals for clinical ART management in Kenya. This study however,. expands virologic failure ssessment to include therapeutic drug level (TDL) monitoring, and the longer duration between VL1 and VL2 would otherwise not change the virologic response status determination, although failing patients may not benefit from timely clinical decisions. We show that adherence significantly affects virologic outcomes and plasma cNVP: good adherence was associated significantly with suppressed VL and higher cNVP while poor adherence was associated with significantly high VL and lower (sub-therapeutic) cNVP levels. Moreover, TDL was predictive of virologic and adherence outcomes; attainment of early peak cNVP (4 hours post dosing) was significantly consistent with lower viral load and predictive of virologic success while patients achieving delayed peak cNVP (24 hours) were likely to fail treatment in multivariate tests. In a study conducted in Malawi to examine factors that affect treatment outcomes in patients receiving ART, up to 47% of the subjects were non-adherent to treatment . That stAccumulating evidence show that community support networks (CPS) enhances social relationships that demystify HIV-associated stigma , 38. We ART management in Kenya at the time of the study followed existing national guidelines that included periodic monitoring of VL and CD4 levels , but did


Although most HIV-infected individuals achieve undetectable viremia during antiretroviral therapy (ART), a subset have low-level viremia (LLV) of varying duration and magnitude. The impact of LLV on treatment outcomes is unclear. We investigated the association between LLV and virological failure and/or all-cause mortality among Swedish patients receiving ART.HIV-infected patients from two Swedish HIV centers were identified from the nationwide register InfCare HIV. Subjects aged ≥15 years with triple agent ART were included at 12 months after treatment initiation if ≥2 following viral load measurements were available. Patients with 2 consecutive HIV RNA values ≥1000 copies/mL at this time point were excluded. Participants were stratified into four categories depending on viremia profiles: permanently suppressed viremia (<50 copies/mL), LLV 50–199 copies/mL, LLV 200–999 copies/mL and viremia ≥1000 copies/mL. Association between all four viremia categories and all-cause death was calculated using survival analysis with viremia as a time-varying covariate, so that patients could change viremia category during follow-up. Association between the three lower categories and virological failure (≥2 consecutive measurements ≥1000 copies/mL) was calculated in a similar manner.LLV 50–199 copies/mL was recorded in 70/1015 patients (6.9%) and LLV 200–999 copies/mL in 89 (8.8%) during 7812 person-years of follow-up (median 6.5 years). LLV 200–999 copies/mL was associated with virological failure , whereas LLV 50–199 copies/mL was not . LLV 200–999 copies/mL had an adjusted mortality hazard ratio of 2.29  and LLV 50–199 copies/mL of 2.19 .In this Swedish cohort followed during ART for a median of 4.5 years, LLV 200–999 copies/mL was independently associated with virological failure. Patients with LLV had higher rates of all-cause mortality, although not statistically significant in multivariate analysis. Although antiretroviral treatment (ART) improves survival and health in people living with HIV (PLHIV), mortality among PLHIV remains elevated compared to that in matched population controls , 2. The Both the underlying cause and potential effects of LLV are unclear. LLV could be due to release of HIV particles from latently infected cells or ongoing virus replication . AlthougApart from the risk of drug resistance and virological failure, it has also been suggested that LLV may be associated with increased mortality –26. HithIn this study, we aimed to investigate whether LLV is associated with a long-term risk of virological failure and all-cause mortality, respectively, in PLHIV receiving ART in Sweden.Participants were identified from a nationwide register, InfCare HIV, that includes >99% of individuals with known HIV infection in Sweden . Data waThis study was conducted with ethical committee approval by the University of Gothenburg Regional Ethical Review Board (DNr: 532–11). All participants gave informed consent upon entering into the register.Patients were stratified into 4 groups depending on their viremia profile: 1) Permanently suppressed viremia (PSV), defined as two or more RNA values <50 copies/mL ; 2) LLV 50–199 copies/mL (LLV-I), defined as two or more consecutive RNA values between 50–199 copies/mL, at least 1 month apart; 3) LLV 200–999 copies/mL (LLV-II), defined as two or more consecutive HIV RNA values ≥50 copies/mL, at least 1 month apart, with at least one value between 200 and 999 copies/mL; 4) High-level viremia ≥1000 copies/mL (HLV), defined as two or more consecutive HIV RNA values ≥50 copies/mL with at least one value ≥1000 copies/mL. Patients with documented interruption of treatment for one month or longer were also included in the HLV group.st January 2005) and CD4 cell nadir . Since injecting drug use (IDU) is associated with greatly increased risk of death in PLHIV . Abbreviations: HR–hazard ratio; CI–confidence interval; IDU–injecting drug use; PSV–permanently suppressed viremia; LLV-I–low-level viremia 50–199 copies/mL; LLV-II–low-level viremia 200–999 copies/mL; HLV–high-level viremia; N/A–not applicable(DOCX)Click here for additional data file.


Pan troglodytes). Surprisingly, however, similar findings have not been reported for chimpanzees experimentally infected with SIVcpz in captivity, raising questions about the intrinsic pathogenicity of this lentivirus.Simian immunodeficiency virus of chimpanzees (SIVcpz), the progenitor of human immunodeficiency virus type 1 (HIV-1), is associated with increased mortality and AIDS-like immunopathology in wild-living chimpanzees (P. t. verus) infected twenty years ago by intrarectal inoculation with an SIVcpz strain (ANT) from a wild-caught eastern chimpanzee (P. t. schweinfurthii). With sustained plasma viral loads of 105 to 106 RNA copies/ml for the past 15 years, this chimpanzee developed CD4+ T cell depletion (220 cells/μl), thrombocytopenia , and persistent soft tissue infections refractory to antibacterial therapy. Combination antiretroviral therapy consisting of emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and dolutegravir (DTG) decreased plasma viremia to undetectable levels (<200 copies/ml), improved CD4+ T cell counts (509 cell/μl), and resulted in the rapid resolution of all soft tissue infections. However, initial lack of adherence and/or differences in pharmacokinetics led to low plasma drug concentrations, which resulted in transient rebound viremia and the emergence of FTC resistance mutations (M184V/I) identical to those observed in HIV-1 infected humans.Here, we report progressive immunodeficiency and clinical disease in a captive western chimpanzee (P. t. verus apes that are not naturally infected with this virus. Moreover, SIVcpz-associated immunodeficiency can be effectively treated with antiretroviral therapy, although sufficiently high plasma concentrations must be maintained to prevent the emergence of drug resistance. These findings extend a growing body of evidence documenting the immunopathogenicity of SIVcpz and suggest that experimentally infected chimpanzees may benefit from clinical monitoring and therapeutic intervention.These data demonstrate that SIVcpz can cause immunodeficiency and other hallmarks of AIDS in captive chimpanzees, including  P. t. troglodytes) in west central Africa and the eastern chimpanzee (P. t. schweinfurthii) in the Democratic Republic of the Congo (DRC) and countries to the east [P. t. verus) and Nigeria/Cameroon (P. t. ellioti) are free of SIVcpz infection [Cercocebus atys) or vervet monkeys (Chlorocebus pygerythrus), is pathogenic in its natural chimpanzee host [SIVcpz infection is common and widespread in two chimpanzee subspecies, the central chimpanzee  was initiated on January 19, 2015, using a combination of the nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), and the integrase strand transfer inhibitor dolutegravir (DTG) at daily doses of 300, 200 and 50 mg, respectively. This regimen was selected because it is recommended for HIV-1 infected adults  and pote50) of TFV (7.8 μg/ml) [90) of FTC (51 ng/ml) and DTG (64 ng/ml) [Cotton received ART daily by oral administration of crushed tablets dissolved in diluted fruit syrup, but caretakers noticed that he did not always ingest his medication completely. We thus continued to monitor his virus load in blood samples obtained during his bi-annual medical evaluations. Indeed, nine months following initiation of therapy 9/25/15), virus was again detectable (4760 RNA copies/ml) in his plasma   and the 4 ng/ml) , 31, res4 ng/ml) , 33. Sin4 ng/ml) , while D4 ng/ml) , the unipol gene sequences from pre- and post-treatment plasma samples. Briefly, plasma RNA was extracted, reverse transcribed, and the resulting cDNA end-point diluted to single template levels. Full-length pol genes were amplified and sequenced, and amplicons comprising more than one variant discarded [pol amplicons, suggesting complete virus suppression.Insufficient drug concentrations are known to facilitate the emergence of drug resistance . We thusiscarded . This aniscarded , 38. Viriscarded  due to tiscarded . Interesenv gene sequences revealed that the majority of rebound viruses fell within the radiation of strains sampled immediately prior to treatment (11/25/14), with only two post-treatment sequences clustering with viruses from 2006  that was RT-qPCR negative is consistent with this  in the first post-treatment sample 3/12/15). Treatment interruptions of fully suppressed HIV-1 infected humans usually result in the emergence of multiple viral lineages –44 that /12/15. Td humans , 49. Altd humans  to estimPts. While Cotton’s laboratory values did not meet the formal definition of AIDS (<200 CD4+ T cells/μl), his low CD4+ T cell counts, high plasma viral loads, treatment refractory soft tissue infections, and marked clinical improvement following reduction of plasma viremia by antiretroviral therapy indicates that SIVcpz caused his immunodeficiency. These results thus dispel the notion that SIVcpz is non-pathogenic in captive environments, or that SIVcpzANT is an attenuated strain [P. t. verus chimpanzees are still alive. One (X176) was reported to have a CD4+ T cell count of 115 cells/μl, which represents an AIDS-defining criterion, while the other (X284) maintained low viral loads and normal CD4 counts 16 years after infection [In summary, we report here the first case of progressive immunodeficiency and clinical disease in a western chimpanzee experimentally infected with a naturally occurring strain of SIVcpzd strain . They alve. One X6 was repWe also show that SIVcpz associated immunodeficiency can be effectively treated with antiretroviral therapy, which decreased plasma viremia in Cotton to undetectable levels within 7 weeks and increased CD4+ T cell counts to above 500 cells/μl within 2 years after onset of therapy, although low plasma drug concentrations resulted in the emergence of FTC resistance mutations. A considerable number of HIV-1 and SIVcpz infected chimpanzees are still housed in US primate centers. This study, together with previous reports of disease progression in HIV-1 infected captive chimpanzees –53, indi