The advent of HAART has been associated with a profound reduction in morbidity and mortality from HIV/AIDS. However, side effects and toxicities associated with HAART may lead to an increased risk for cardiovascular diseases. The aim of this study was to determine the prevalence of dyslipidemia and determining factors of derangements in lipid profile associated with the use of HAART regimens in people living with HIV/AIDS in Fako Division of the South West Region of Cameroon.t-test, ANOVA and logistic regressions were computed.This cross-sectional study was conducted between March and August 2014. Lipid profile was determined after overnight fast and dyslipidemia diagnosed according to the US National Cholesterol Education Program III criteria. Socio-demographic characteristics were also collected using a questionnaire. Data was analyzed using STATA; chi-square test, student’s + T cell count was 425 (±281) cells/μl after mean duration of HIV infection of 54.8 (±43.9) months and mean duration on ART of 63.7 (±41.4) months. The prevalence of total cholesterol (≥ 200 mg/dL) was 51.0 % in patients on HAART and 9.6 % pre-HAART patients (p < 0.0001), whereas LDL-cholesterol ≥ 130 mg/dL occurred in 36.9 % and in 7.7 % respectively, (p = 0.0001). Receiving HAART  and HIV duration of 42 months and more  were independently associated with total cholesterol ≥ 200 mg/dL. Receiving HAART  was independently associated with raised LDL-cholesterol values. The adjusted odds ratio (95 % CI) of BMI ≥ 25.0 kg/m2 versus BMI < 25.0 kg/m2 was 3.25 (1.44–7.34) for triglycerides ≥ 150 mg/dL.Two hundred and nine participants were recruited including 157 (75.1 %) on HAART and 52 (24.9 %) HAART-naïve. Antiretrovirals were drugs containing two nucleoside backbones (zidovudine/ /lamivudine/tenofovir) with either a non-nucleoside (nevirapine/efavirenz) or a protease inhibitor (lopinavir). No patient was treated with statins. Their mean age was 43.4 (±11.0) years. The mean CD4HAART regimens were significantly associated with atherogenic lipid profile. Lipid profile should be monitored in HIV/AIDS patients on therapy so that any negative effects of HAART are optimally managed. The introduction and widespread use of combination antiretroviral therapy (ART) referred to as highly active antiretroviral therapy (HAART) in the mid 1990’s, has led HIV-infected individuals to experience a dramatic decline in immunodeficiency-related events, including causes of death . HoweverThis was a hospital-based cross-sectional study. Participants were recruited between March and August 2014 at treatment centers of people living with HIV/AIDS (PLWHA) in the Limbe and Buea Regional Hospitals in Fako Division, South West Region of Cameroon. Two groups of participants were selected. Group one was made up of individuals living with HIV/AIDS who had been receiving HAART for at least 6 months and reported by the treatment centres as non-defaulters (ART group). The second group was made up of individuals newly diagnosed with HIV but who were not yet receiving HAART (ART-naïve group). All participants were 21 years of age and above. Participants receiving lipid altering therapies, pregnant women, known diabetes mellitus patients, those with renal failures and patients who refused to be part of the study were excluded.+ T cell count, HIV and HAART status. Body mass index and blood pressure were also measured. About 5 ml of venous blood sample was collected from each participant through venipuncture after a 12 h overnight fast and centrifuged at 2500 cycles/min for 10 min, and serum was obtained for fasting blood sugar and lipid profiles measurements. Fasting blood sugar and lipid profile were assessed through enzymatic methods  for all participants including total cholesterol (TC), high density lipoprotein cholesterol (HDL-c), low density lipoprotein-cholesterol (LDL-c) and triglycerides (TG). The TC/HDL-c ratio was also calculated. In accordance with the US National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATP III) guidelines, abnormal lipid profile was defined as TC ≥ 200 mg/dL, HDL-c < 40 mg/dL, LDL-c ≥ 130 mg/dL, TG ≥ 150 mg/dL and TC/HDL-c ratio ≥ 5 , were currently receiving HAART; the second group of 52 HIV-infected patients , were HAART inexperienced. The mean age of individuals who were on HAART was 44.9 (±10.7) years while that of pre-HAART was 38.8 (±10.8) years (Table p < 0.001). The mean TG and TC/HDL-c were significantly higher in participants on HAART than their HAART inexperienced counterparts (p < 0.05). There was no statistically significant difference between the two groups for mean HDL-c (Table The mean TC and mean LDL-c were significantly higher in patients on HAART than in HAART-naïve patients (-c Table . The pre-c Table .Table 2Sp = 0.009 and 0.004 respectively) (Table p = 0.0604).The mean TC was higher in patients on TDF than those on AZT among the nucleoside reverse transcriptase inhibitor (NRTIs) based treatment. Among the non-nucleoside reverse transcriptase inhibitor (NNRTIs) based treated patients, the mean TC was also higher in patients on EFV compared to NVP. Although this was not statistically significant, it was above the normal cut off point. The mean TG was statistically significantly higher in patients on TDF compared to AZT, and EFV compared to NVP (y) Table . No signy) Table . No sign+ T cell count categories. HAART experienced participants with CD4+ T cell counts < 200 cells/μl and ≥ 500 cells/μl had higher mean TC values (227.9 (±70.7) and 230.0 (±101.7) respectively. No significant difference was found between mean values of lipid derangements and presence or absence of hypertension and diabetes mellitus. However, hypertensive patients had higher mean values of raised TC (203.1 ± 80.6) compared to non-hypertensive (190.6 ± 68.3) (p = 0.2942). Obese patients had higher mean values of raised TC (218.4 ± 83.1) compared to the non-obese (185.9 ± 65.7) (p = 0.0052). Also, obese patients had higher mean values of LDL-c (128.5 ± 76.5) compared to the non-obese (97.7 ± 61.7) (p = 0.0045).No significant difference was observed in the mean lipid profile parameters in the different CD4p = 0.042). The BMI of 25 kg/m2 and higher was significantly associated with raised TG . The duration of HIV infection of 42 months and higher was significantly associated with raised TC and increased TG (p = 0.045 and 0.035 respectively). The odds ratio (95 % CI) of HIV infection duration of 42 months and higher versus less than 42 months was 0.51 (0.26-0.99) for TC ≥ 200 mg/dL and 0.36 (0.14-0.93) for TG ≥ 150 mg/dL. Being on HAART treatment for more than 55 months was significantly associated with raised TC and raised TG, with 95 % CI odds ratio of 0.47 (0.25-0.90) and 0.31 (0.13-0.74) respectively . The adjusted odds ratio (95 % CI) of HAART-treated versus HAART-naïve was 6.24 (2.33–17.45) for TC ≥ 200 mg/dL and 5.28 (1.17–16.32) for LDL-c 130 mg/dL. Antiretroviral therapy was not positively associated with decreased HDL-c, increased TG and raised TC/HDL-c ratio . Raised body mass index (BMI ≥ 25.0 kg/m2) was significantly and positively associated with increased TG . The duration of HIV infection of 42 months and higher was significantly and positively associated with raised TC . HAART treatment was positively associated with the ratio of TC/HDL-c but this was not significant  in HIV patients receiving HAART. Though high, the prevalence of dyslipidemia in our study is similar to the reported rate of 70.2 % in patients receiving ART in a rural Cameroonian population [The aim of this study conducted in a resource-poor setting was to determine the prevalence of dyslipidemia and determining factors of derangements in lipid profile associated with the use of HAART regimens in HIV/AIDS patients. We found that CD4olleague  where CDpulation , but lowpulation , and 76.pulation . We founpulation , and werpulation , 15, andpulation , where ppulation , and simpulation . Howeverpulation , and Indpulation , but simpulation . We founpulation  in whoseSeveral studies have found that stavudine was more involved in the occurrence of lipid derangements as compared with other NRTIs –22. HoweThe association between HAART and adverse lipid profile has been largely described for regimens that include PIs , 24, but+ T cell counts gave a snapshot of disease progression in the untreated group and disease suppression in the treated group. Comprehensive cardiovascular risk stratifications were not assessed in this study. However, the increased risk of atherothrombotic cardiovascular disease associated with the described lipid derangement is well known [There is lack of data on HIV viral load to clearly define disease stages in the two groups. However, the CDll known , 29 and This study indicates that HIV-infected patients receiving WHO-recommended HAART treatment have a high prevalence of lipid profile derangements when compared to the HAART non-treated HIV-infected patients. Uses of HAART regimens are significantly associated with atherogenic lipid profiles. Lipid profile and other cardiovascular risk factors should be monitored in patients on ART so that any negative effects of HAART can be optimally managed. We recommend the implementation of well controlled cohort studies for the evaluation of long-term effects of HAART treatment on lipid profiles.


Conducted in Wuhan China, this study examined follow-up and health markers in HIV patients receiving care in two treatment settings. Participants, all men who have sex with men, were followed for18–24 months.Patients in a “one-stop” service  vs those in standard care clinics  were compared on HIV treatment and retention in care outcomes.p = 0.000), proportion with HIV suppression for patients receiving cART for 6 months , proportion with CD4 cell recovery for patients receiving cART for 12 months , median time from HIV confirmation to first test for CD4 cell count  and median time from first CD4 cell count ≦350 cells/µL to cART initiation . Clinic groups did not differ on any biomedical indicator at baseline, and no baseline biomedical or demographic variables remained significant in the multivariate analysis. Nonetheless, post-hoc analyses suggest the possibility of self-selection bias.Among patients with CD4 cell count ≦350 cells/µL, the proportion receiving cART did not differ across clinic groups. The ACC was favored across five other indicators: proportion receiving tests for CD4 cell count at the six-month interval (98.2% vs. 79.4%, 95% CI 13.3–24.3, Study findings lend preliminary support to a one-stop patient-centered care model that may be useful across various HIV care settings. HIV/AIDS is found in all regions of China Chinese investigators Improving the clinical care experience could help patients to achieve higher levels of participation and retention in health care and in cART protocols in particular, leading to prolonged survival Emphasizing the commonalities between HIV management and other chronic disease care, other observers have called for a self-management model with patients assuming an active and informed role in healthcare decision making The literature on “one stop”/integrated HIV care offers useful program guidelines, but few studies have formally evaluated these models of care. The present study in central China examined patient outcomes in a new “one-stop” care program and in existing clinics.Under China's “Four Free and One Care” policies The National CDC subsequently outlined a “Treatment 2.0” plan for China, and the Wuhan CDC was the first site to initiate a pilot project integrating a range of public health resources within a “one-stop” service delivery protocol for individuals with HIV/AIDS infection. The intent of the present comparison study is to describe the treatment experience, follow-up participation and disease progression among patients who chose to enroll in either one of two delivery models of HIV/AIDS care.The CDC-initiated Wuhan AIDS Care Center (ACC) is a comprehensive “one-stop” program for people living with HIV (PLHIV). The pilot effort was initiated at a single clinic, permitting a comparison of the demonstration project and standard care provided in the existing CDC system. The new clinic included counseling, testing, diagnosis, treatment and health education provided by physicians, nurses and workers from community-based organizations (CBOs) serving MSM. The “one-stop” services included cART provision, regular follow-up, referral for Tuberculosis (TB) screening and treatment, referral for AIDS-related or non-AIDS-related diseases, risk behavior prevention, and psychological support. The ACC maintained close linkages with district CDCs, the Tuberculosis Institute, comprehensive general hospitals, and the designated AIDS hospital . The ACC provided as many services as possible within the facility; when additional services, such as diagnosis and treatment of TB, were needed, ACC staff actively linked the patient to other elements within the CDC system. For example, ACC staff often telephoned collaborating health care providers in the presence of the patient and routinely followed up with patients to be sure that the referral was completed and to inquire about patient's understanding of the test, procedure or consultation. The ACC trained members of CBOs on knowledge and skills of HIV prevention and provides AIDS/-related materials and condoms. The CBOs coordinated closely with the ACC, and assigned staff to the ACC clinic to work directly with patients. CBO staff provided a range of services including referral, transportation, information and emotional support. As stigma is inversely associated with HIV testing and treatment adherence Patients in the usual-care CDC clinic could potentially access the same kinds of services available to patients in the ACC clinic; however, some districts provide a range of services within the primary care clinic or in nearby facilities, while others offer only basic care. The comprehensiveness of care depends on the degree to which the primary health care provider is aware of what is available and the degree to which effective linkages are made. All CDC clinics included counseling, testing, health education, cART provision, and regular follow-up.All 13 CDC districts/clinics were involved in the study; of these, only two provide extensive services within the primary care clinic, while others offer limited care, such as blood pressure, blood sugar and routine assays of blood and urine etc. In all districts in Wuhan, specific tests  are conducted in a designated AIDS hospital with expertise in HIV and other contagious diseases.The major ACC vs CDC distinctions were the service providers and the service delivery arrangements. The CDC clinics only have public health workers; the ACC has physicians, nurses and workers from CBOs. Some CBOs refer patients to CDC units, but CBO staff do not work at CDC clinics. CDC patients did not receive peer education, psychological support, or other services provided by CBO staff. For CDC patients, the relevant clinical assays were conducted upon referral to nearby facilities; e.g., tests for HIV-RNA and CD4 were carried out after referral to Wuhan CDC. cART-related side effects and other clinical conditions were referred to the designated AIDS hospital or comprehensive hospitals; whereas, for ACC patients, all of these procedures and protocols, except TB screening, were performed in the ACC setting.The enrollment period spanned July 1, 2011 to June 30, 2012; the final follow-up assessment was December 31, 2013. Demographic and biomedical data for all patients were recorded at baseline and relevant biomedical data were obtained at follow-up interviews. ACC patients were followed on a quarterly basis and the usual-care CDC patients were followed on a semi-annual schedule.Each follow-up visit included: a physical examination for basic health conditions including breath frequency, heart rate, blood pressure and body weight; indicated screening for sexually transmitted infections and tuberculosis; routine assays of blood and urine , tests for alanine aminotransferase (ALT), blood urea nitrogen (BUN) and CD4 cell count. ACC and CDC patients received respectively two and one HIV-RNA tests annually. In both the ACC and CDC clinics, staff sought to begin CD4 cell counts soon after a confirmatory HIV test and to begin cART immediately following a cell count ≦350 cells/µL. cART was delayed for a few patients , when immediate initiation of antiretroviral treatment was contraindicated.In the follow-up assessments, date-anchored CD4 counts, HIV-RNA tests and cART treatments were used to determine health status across six health care indicators (HCIs), four relevant to HIV treatment and patient adherence, and two measuring recognized markers of disease status The Institutional Review Board of Wuhan CDC approved this study, and written informed consents were obtained from all the patients.2) test and Fishers exact probability test or the Mann-Whitney test. If abnormal distributions were found, the Wilcoxon rank sum test was used. Median times to test for CD4 cell count and cART initiation were compared through Kaplan-Meier curves and log rank tests. Cox proportional hazards regression was used to identify factors influencing adherence. Statistical tests were two-sided with alpha  = 0.05.Data were analyzed with the software SAS version 9.13 . Categorical data were compared with the chi-square (χp = 0.012). More ACC patients had temporary or permanent jobs, whereas larger proportions of the CDC group were unemployed or students (p = 0.000). At baseline, the two groups did not differ significantly on any of ten clinical tests. Approximately two-thirds of patients reported having never been married  and 1.94 person-years (IQR 1.64–2.21). ACC patients ranged in age from 18–68, with an average age of 32.7 . CDC patients ranged in age from 16–82, and their average age was 34.7 (95% CI 32.9–36.3). Many participants had a junior college or higher degree, but the education of ACC patients was higher than that of CDC patients  had CD4 cell counts of ≦350 cells/µL, 59.1% (52/88) received cART treatment, including 36 patients with CD4 cell count ≦350 cells/µL and 16 with CD4 cell count>350 cells/µL; 90.4% (47/52) were followed for 18–24 months. A total of 243 CDC patients were initially observed, but 11(4.5%) moved away or provided inaccurate contact information. Of the remaining 232 patients, 54.3% (126/232) received cART treatment, including 124 patients with CD4 cell count ≦350 cells/µL and two patients with CD4 cell count>350 cells/µL; 67.5% (85/126) were followed for 18–24 months.Nine CDC patients died, a mortality rate of 3.97 per 100 person-years (95% CI 1.50–6.44). Their median age was 46 (39–82); their median CD4 cell count at baseline was 204 (5–791) cells/µL; the mean time between HIV confirmation and death was 38 (1–481) days; six died prior to initiation of cART. Causes of death were AIDS-related opportunistic infections (6), suicide (2) and acute myocardial infarction (1). No ACC patients died. Baseline health indicators of drop-out and deceased cases within the CDC clinic are shown in As presented in p = 0.000). The variables related to HCI 4 were clinic setting , baseline ALT value , baseline CD4 cell count .Cox proportional hazards regression was used to identify predictors of HCI 1, HCI 3 and HCI 4. For HCI 1, independent variables included clinic setting and four socio-demographic variables listed in table1. For HCI 3 and HCI 4, independent variables included clinic setting, four socio-demographic variables, ten health-related conditions listed in Consistent medical follow-up is essential for measuring patients' disease progression, monitoring treatment effects and providing health education and behavioral intervention Treatment outcome determination cannot entirely disentangle measurement follow-up from the monitoring components of the intervention itself The substantial differences in mortality between the ACC (0) and CDC (9) groups were unexpected. Six of nine deaths occurred within six months of enrollment. Compared to the CDC patients who lived, the deceased patients were substantially older, and, at baseline, had lower CD4 cell counts and were more likely to have abnormal hemoglobin values . Becausep = 0.001). Missing data would have little effect on HCIs 2, 3, 4 and 6, as these outcomes were assessed only for those participants whose CD4 counts were almost always less than 350 cells/µL–while all drop-outs had high CD4 counts. It appears unlikely that the loss of cases biased study results.No cases are missing for indicator 5. For indicator 1, data are missing for the six individuals who died within the initial 6-month follow-up period. The between-group result was virtually the same when missing cases were replaced and imputed a positive value for “complete CD4 count at six months” (98.9% [88/89] vs. 87.2% [212/243], As noted above, interpretations of a non-randomized study must always include the possibility that unmeasured variables account for observed between-group differences. Another important study limitation is the potential heterogeneity in the quality of HIV care within the CDC and ACC clinics. The CDC clinics do not have physicians, only public health workers who distribute cART drugs to patients under the guidance of physicians and other staff with substantial clinical training. Although the ACC was designed as an integrated care unit, it is also possible that the structure and focus of the clinic improves the expertise of the health care providers in any number of ways that were not measured in the present study. The more favorable outcomes among patients in the ACC could be due at least in part to staffing with more highly trained personnel, and a milieu of excellence–not only the integration of care. It should be noted, however, that all CDC staff had been trained for cART provision, follow-up and basic care since 2004, and were regularly monitored by Wuhan CDC. Likewise, the ACC protocols were carefully specified, but perhaps not with the degree of precision found in a randomized clinical trial. For example, the ACC protocols did not prescribe or track the elements of the ACC partnership with CBOs, nor assess how these supportive services may have addressed stigma, homophobia, and discrimination faced by MSM, which, in turn may have favorably interacted with targeted clinical outcomes.In sum, study findings favored the one-stop care model over the existing service model on five of six indicators, including time from initial HIV test to initial CD4 cell count, proportion of patients receiving CD4 cell count at six-months, time between the first indication of a CD4 cell count ≦350 cells/µL and the initiation of cART, CD4 cell recovery and viral suppression. Follow-up outcomes for the CDC patients, and the ACC patients in particular, compare favorably to the markers cited in the studies discussed above on follow-up participation, viral load and CD4 count.Only 27% of patients chose the ACC clinic; as noted, the reimbursable fee may have been a disincentive. Patients who were referred by the hospital may have believed that the CDC—already known to them–could protect their confidentiality better than the unknown ACC. Notwithstanding the clinical similarity of the two clinic groups at baseline, it is possible that men who were feeling relatively well and had a positive attitude about their future were more likely to be attracted to the ACC clinic.Interpretations of the unexpected differential mortality between groups are problematic, given the limitations of a non-randomized study. The profile of the nine deceased CDC patients is quite distinct from that of the overall study group, and it is unknown whether these patients might have lived longer had they enrolled in the ACC clinic. Very sick patients nearing death may not have wished to enroll in an unknown clinic.Incorporating many of the recommendations in the WHO “Treatment 2.0” initiative of 2010, the ACC clinic described herein was the first site in China to initiate a pilot project specifically designed to substantially improve health care services for people living with HIV infection. The program included a comprehensive array of services including testing and diagnosis, treatment and monitoring, counseling and health education, provided by physicians, nurses and workers from community-based organizations serving MSM. The “one-stop” program was favored on three of four process indicators of care, and on indicators of CD4 cell recovery and viral suppression. Albeit compromised by possible self-selection bias, study findings are consistent with existing recommendations concerning the feasibility of the “one- stop” patient-centered approach to care of persons with HIV/AIDS.Future studies, including designs employing randomization, could isolate specific program elements accounting for favorable patient outcomes. Also needed are replication efforts across other areas and settings, particularly those measuring the effectiveness, benefits and costs of various program designs within an overall framework of patient-centered care. Although strong claims of “effectiveness” are not possible in a comparison across self-selected groups, results from this study lend further support to a “one-stop” approach to health care for persons with HIV disease.


Protease inhibitor monotherapy is associated with more frequent episodes of viral rebounds above 50 copies/mL than triple therapy. Objective: To evaluate if, compared to triple-drug therapy, protease inhibitor monotherapy is associated with increased levels of inflammatory/procoagulant markers and more frequent plasma residual viremia detection.In this cross-sectional study, we included patients treated for ≥ 1 year with darunavir/ritonavir or lopinavir/ritonavir as monotherapy (n = 72) or with two nucleos(t)ides (n = 74). All samples were tested for CRP, IL-6, fibrinogen and D-dimer. Residual viremia was determined using an ultrasensitive qualitative nested-PCR of the HIV pol gene with a limit of detection of 1 copy of HIV-RNA.We found no differences in levels of inflammatory/procoagulant markers or in the proportion of patients with plasma residual viremia detection by treatment group.The long-term treatment with protease inhibitor monotherapy in the setting of routine clinical practice is not associated with a higher prevalence of plasma residual viremia or more elevated inflammatory/procoagulant markers levels than triple drug therapy. In clinical trials, protease inhibitor (PI) monotherapy (MT) has been effective in maintaining long-term viral suppression in the majority of patients . HoweverIn the MONET clinical trial , virologThe present study is a subanalysis of a parent study comparing neurocognitive impairment in patients treated with protease inhibitor monotherapy or triple drug antiretroviral therapy. Details of this cohort and the recruitment flow-chart have been previously published . We inclAll samples were tested for CRP, IL-6, fibrinogen and D-dimer. Routine determination of viral load was done with Nuclisens EasyQ HIV-1 v2.0 . This technique quantifies the viral load above 20 copies/ml. At the same time-point, plasma RV was determined using an ultrasensitive qualitative nested-PCR of the HIV pol gene with a limit of detection of 1 copy of HIV-RNA. This method is based on the PCR used for single genome sequencing . The locp-value <0.1 in the univariate analysis, were retained in the model. All analyses were performed using the STATA statistical package . All tests were 2-sided, p values <0.05 were considered significant.Sample characteristics were described using absolute and relative frequencies for categorical variables and median (IQR) for continuous variables. Chi-square test and Student’s t or the nonparametric Mann–Whitney U-test were used to compare baseline characteristics. We evaluated predictive factors of increased IL-6, CRP levels using a multivariate lineal regression model on log-transformed data. Explored factors were: age, sex, AIDS, CD4 (nadir/current), prior medical disease, hepatitis C (defined by HCV serum PCR), duration of viral suppression, detection of RV, blips (HIV RNA level > 50 copies/ml) in the last year, group of treatment, type of PI, triglycerides, total cholesterol/LDL ratio, total cholesterol/HDL ratio, HOMA index and use of statins. Variables with a Patients were predominantly male, with a median age of 46 years, and good immune status Table . CompareWe found no differences in levels of inflammatory/procoagulant markers between groups of treatment. Specifically we have not found differences in IL-6 levels ≥3 pg/mL and CRP levels ≥ 5 mg which have been associated with higher rates of progression to AIDS or death and an increased cardiovascular risk . These rWe have found that the use of PI MT in routine clinical practice, compared to TT, is not associated to higher levels of inflammatory or procoagulant markers. Interestingly, as in prior studies ,8 hepatiIn our study, plasma RV -detectable in nearly half of patients- was not more frequent in patients receiving MT. In the “Only Kaletra” pilot trial  the leveOur study did not show an association between detection of RV and higher levels of inflammatory/procoagulant markers. In the study by Chun et al.  RV was dOur study has the intrinsic limitations of cross-sectional analyses. We compared MT and TT in a selected group of patients, who have maintained long-term virological suppression and results cannot be extrapolated to other types of patients. However this limitation is inherent to the fact that MT is only indicated in adherent patients with suppressed viral load . The timIn summary, our study suggests that long-term treatment with darunavir/ritonavir or lopinavir/ritonavir MT in the setting of routine clinical practice is not associated with a higher prevalence of plasma RV or more elevated inflammatory/procoagulant markers levels than triple drug therapy.The authors declare that they have no competing interests.ME and JRA conceived of the study, and participated in its design, coordination and wrote the draft. NS and JM carried out the nested-PCR assays. IPV, JIB, FXZ and MLM participated in the design of the study, inclusion of patients and helped in the statistical analysis. JGG helped in the coordination and drafted of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/14/379/prepub


In West and Central Africa Buruli ulcer (BU) and HIV co-infection is increasingly recognised and management of these two diseases combined is an emerging challenge for which there is little published information. In this case we present a severe paradoxical reaction occurring after commencing antibiotic treatment for BU combined with antiretroviral therapy for HIV, and describe its clinical features and management. This includes to our knowledge the first reported use of prednisolone in Africa to manage a severe paradoxical reaction related to BU treatment.A 30 year old immunosuppressed HIV positive man from Cameroon developed a severe paradoxical reaction 24 days after commencing antibiotic treatment for BU and 14 days after commencing antiretroviral therapy for HIV. Oral prednisolone was successfully used to settle the reaction and prevent further tissue loss. The antiretroviral regimen was continued unchanged and the BU antibiotic treatment not prolonged beyond the recommended duration of 8 weeks. A second small local paradoxical lesion developed 8 months after starting antibiotics and settled with conservative treatment only. Complete healing of lesions occurred and there was no disease recurrence 12 months after commencement of treatment.Clinicians should be aware that severe paradoxical reactions can occur during the treatment of BU/HIV co-infected patients. Prednisolone was effectively and safely used to settle the reaction and minimize the secondary tissue damage.The online version of this article (doi:10.1186/1471-2334-14-423) contains supplementary material, which is available to authorized users. Mycobacterium ulcerans causes severe destructive lesions of skin, soft-tissue and bone mediated through its potent exotoxin mycolactone that are known as Buruli ulcers (BU). They are most commonly found in Central and West Africa but have been reported from Australia, Asia, South America and the Pacific [ Pacific . It pred Pacific –4. Parad Pacific  and can  Pacific . Prednis Pacific  but its  Pacific .In this case we present a severe paradoxical reaction occurring in a patient co-infected with BU/HIV after commencing antibiotic treatment for BU concomitantly with ART for HIV. We describe its clinical features and management including to our knowledge the first reported use of prednisolone to manage a severe paradoxical reaction related to BU treatment in Africa.A 30 year old man living in rural Cameroon presented to the Buruli ulcer treatment center in Akonolinga, Cameroon, in January 2013 with a 7-month history of plaque-like lesions over the lateral aspect of this left ankle and posterior aspect of his left leg both of which later ulcerated. The ulcer on the lateral aspect of the left ankle measured 14 cm x 9 cm with some small areas of necrosis and inflammation in the surrounding tissue. The second ulcerative lesion on the left leg measured 6 cm x 4 cm with minimal surrounding inflammation. Xrays of the left ankle and left leg revealed no evidence of osteomyelitis deep to the lesions. His weight was 65 kg and Body Mass Index 25. Further examination was unremarkable with specifically no clinical evidence of co-infection with tuberculosis and a chest X-ray was normal.3. Baseline viral load was not available.He had been previously diagnosed elsewhere with HIV infection and received 2 months of ART from January 2012 but had then interrupted it. A HIV antibody test on presentation to Akonolinga was positive and a CD4 count was 212 cells/mmThe diagnosis of BU was made on the basis of a positive AFB stain and compatible histopathology showing a granulomatous infiltrate on tissue biopsies, and a positive IS2404 PCR and AFB stain on swab specimens, of both the ankle and leg lesions.He was hospitalised and commenced on BU treatment with oral rifampicin 600 mg daily and intramuscular streptomycin (STM) 1 gram daily on 9/1/13. Within 24 hours he developed a fever to 39.5 degrees and a generalised pustular and itchy rash. A diagnosis of a STM hypersensitivity reaction was made and the STM was replaced by clarithromycin 500 mg twice daily. Prednisolone 30 mg orally daily was also given for 10 days and the reaction resolved.Antiretroviral treatment (ART) was commenced on 19/1/13 with a regimen containing zidovudine, lamivudine and efavirenz. Co-trimoxazole 960 mg/day was also commenced at the same time. Antibiotic and ART adherence was directly supervised in the hospital.Two weeks after ART initiation the tissue around the ulcer became inflamed, with significant oedema extending across the dorsum of the foot to the toes with evidence of extending necrosis and ulceration from the wound margins. Figure  and was 3.A further 1 cm ulcerated lesion on the retromalleolar region of the left ankle appeared 8 months after the start of BU antibiotic treatment.  and ART was commenced early (2 weeks) after the start of BU treatment. Furthermore the good response to his ART with a robust increase in his CD4 cell count and reduction in viral load to undetectable levels may have contributed. A recent report from Ivory Coast also describes further multifocal BU lesions developing in a HIV positive patient with severe immunosuppression (baseline CD4 count of 51 cells/mm3) one month after starting both BU antibiotic treatment and ART [It is not known whether paradoxical reactions are increased in HIV patients with BU, whether this is influenced by the baseline level of immune suppression or whether it is further potentiated when the generalised immune suppressed state is partially reversed by ART. However it is known that paradoxical reactions are common in HIV patients commencing ART with a variety of other microorganisms including tuberculosis (TB) , cryptoc and ART . Further and ART .Oral prednisolone was used in this patient to settle a severe paradoxical reaction. We believe it prevented further skin and subcutaneous tissue loss on the dorsum of the foot, which commonly occurs during treatment of oedematous BU lesions and with severe paradoxical reactions . EvidencThis case also illustrates a number of important issues relevant to the patient co-infected with BU and HIV. Firstly the patient presented with large, multiple and ulcerated lesions consistent with previous reports of more severe BU disease at presentation in those co-infected with HIV , 4. SecoSevere paradoxical reactions can occur during the antibiotic treatment of BU/HIV co-infected patients. Prednisolone was effectively and safely used to settle the reaction and minimize the secondary tissue damage. Further study on the incidence, risk factors and management of paradoxical reactions in HIV/BU co-infected populations is needed.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.


In the snapshot analysis HIV-RNA was below 50 c/mL in 72.5/65.9/51.6%, respectively, and >50 c/mL in 6.6/5.4/4.3%. Only 0.8/1.9/3.5% discontinued due to adverse events. There was a high rate of discontinuations due to other reasons or with VL missing in window. In a multivariate adjusted analysis, we observed an association between VF and nadir CD4 count , time with VL≤50 c/mL  and previous failure with a PI . There was no association with gender, age, hepatitis virus co-infection, CD4 count at time of switching or third drug used in the previous regimen.400+ABC/3TC in selected subjects with HIV-RNA below 50 c/mL is associated with relatively low rates of VF and discontinuation due to adverse events. Use might be considered in those with long-term suppression and without prior PI failure. Larger cohorts are required to further define the appropriate selection criteria.A switch to ATV


The reduction in circulating inflammatory cytokines levels may be partly responsible for the efficacy of peritoneal dialysis for refractory congestive heart failure.Proinflammatory cytokines play a pathogenic role in congestive heart failure. In this study, the effect of peritoneal dialysis treatment on inflammatory cytokines levels in refractory congestive heart failure patients was investigated. During the treatment, the patients reached a well-tolerated edema-free state and demonstrated significant improvement in NYHA functional class. Brain natriuretic peptide decreased significantly after 3 months of treatment and remained stable at 6 months. C-reactive protein, a plasma marker of inflammation, decreased significantly following the treatment. Circulating inflammatory cytokines TNF- Removal of extensive fluid overload is one of the most difficult challenges in the management of severe congestive heart failure (CHF), particularly in patients who are refractory to diuretic therapy. Peritoneal ultrafiltration (UF) is a simple choice for daily fluid removal. Today, peritoneal dialysis (PD) is increasingly used to treat hypervolemic CHF patients who are resistant to conventional therapies, in particular when complicated by renal insufficiency . It α), which mediate, via specific receptors, various processes as gene expression, cell growth, or apoptosis [The link between HF and inflammation was recognized and reported in 1990 by Levine et al. , who notpoptosis –16.β) and interleukin-10 (IL-10), which can downregulate the production of several inflammatory cytokines from macrophages and other cells [Myocardial expression of cytokines contributes to depression of contractile performance and adverse LV remodelling. Cytokine-induced decreased contractile performance appears to result from sphingosine production, which interferes with myocardial calcium handling . The acter cells , 18. Perer cells –22 and cWhile emerging as an effective treatment option for refractory heart failure, peritoneal dialysis may by itself contribute to systemic inflammation (reviewed in ). The coThis study was designed to evaluate the net effect of peritoneal dialysis on circulating inflammatory and anti-inflammatory cytokine levels in patients with refractory CHF and fluid overload.Patients with refractory CHF who were referred by their cardiologists to our PD unit between March 2012 and July 2014 and completed at least 3-month period of follow-up were enrolled into this study. The study protocol was approved by the Sheba Medical Center Institutional Human Research Board. All patients were in NYHA functional class IIIb or IV and showed symptoms and signs of severe cardiac failure with volume excess. They were receiving maximal therapy according to the heart failure guidelines including dietary fluid and salt restriction and maximal tolerable drug treatment, including diuretics, loop and distal tubule (metolazone), angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blockers (ARB), beta-blockers, and digoxin. Some patients were also treated with intravenous furosemide and vasoactive agents in a CHF day care center. The inclusion criteria for PD were all of the following: (1) NYHA functional class IIIb or IV; (2) an echocardiographic evidence of significant left or right ventricular dysfunction, valvular heart disease, or pulmonary hypertension; (3) significant volume overload despite maximal doses of diuretics or repeated episodes of deteriorating kidney function  during the intensification of diuretics treatment or recurrent hospitalization for volume overload in the preceding 3 months. Patients with contraindication for PD  or those incapable of learning and complying with the procedure of PD were excluded from the study. PD catheter was implanted by surgical dissection under local anesthesia in the operating room. In patients with ascites, peritoneal centesis was started by a specially trained PD nurse a day after Tenckhoff catheter insertion. In patients with significant volume overload, small volume exchanges  were performed in the recumbent position by dialysis nurse starting the day after catheter placement. Until the patient and/or family member have learnt the dialysis technique , UF was performed by a PD nurse in the PD unit every day or every other day.The following clinical parameters were collected: disease etiology and functional status (NYHA), preserved/reduced LV function, comorbidities and medications, body weight, and mean arterial blood pressure. Assessment of fluid status was based on clinical examination. Laboratory investigations included serum hemoglobin and leukocyte count, serum albumin, sodium, urea, creatinine, uric acid, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Primary kidney disease was defined as urine protein >0.5 g/24 h, abnormal urine microscopy, and/or abnormal renal sonography . Patients with urine protein <0.5 g/24 h, normal urine microscopy, and normal kidneys per sonography were classified as having cardiorenal syndrome. Echocardiographic parameters used in the study included LVEF and RVEF and systolic pulmonary artery pressure (SPAP). Glucose- and non-glucose-containing (icodextrin) dialysis solutions  were used in the study. Data on the type and volume of PD solutions used by the patient and daily peritoneal UF volume were gathered.α, IL-6, and IL-10 were assessed by enzyme-linked immunosorbent assay (ELISA) according to supplier protocols (R&D systems). This assay employed the quantitative sandwich enzyme immunoassay technique. The cut-off or lower limit of sensitivity was 0.106 pg/mL for TNF-α, 0.039 pg/mL for IL-6, and 0.09 pg/mL for IL-10.Plasma levels of TNF-BNP was measured using the Alere Triage BNP Test, a rapid fluorescence immunoassay kit.t-test. Data in Figures t-test. Differences were considered significant for P < 0.05.The data are presented as median and range for continuous variables and as absolute numbers and percentages for categorical variables. Data presented in The clinical, biochemical, and echocardiographic characteristics of the patients at baseline, prior to beginning of PD, are presented in P = 0.0001). P = 0.0035). Blood hematocrit increased significantly during the treatment from median of 32.51 (19.03–42.68) to 34.84 (30.19–48.28) at 3 months (P = 0.0156) and to 34.29 (28.94–46.19) at 6 months . All patients reached a well-tolerated edema-free state during the first months after starting PD. By the end of the first 3 months of treatment, body weight of CHF patients decreased significantly due to fluid loss . The medP = 0.0259) at 3 months and measured 1062 (161–2720) pg/mL (P = 0.0385) at 6 months.Elevated pretreatment circulating BNP levels were found in all patients . BNP levP = 0.0139) at 3 months and was 5.78 (0.74–55.09) mg/L (P = 0.0375) after 6 months of PD.Baseline C-reactive protein  was apprα level (P = 0.0313) at 3 months and measured 4.02 (2.52–7.01) pg/mL (P = 0.0028) after 6 months of PD.Circulating TNF-α level  decreaseP = 0.0004) at 3 months and was 11.68 (2.22–24.43) pg/mL (P = 0.0133) after 6 months of PD.Circulating level of IL-6  decreaseP = 0.056) at 3 months and remained undetectable (range 0–2.6) pg/mL (P = 0.0974) at 6 months.Median serum anti-inflammatory cytokine IL-10 levels  decreaseα and IL-6 decreased unsignificantly in patients with preserved LV function. Circulating TNF-α level decreased from median of 5.97 (3.9–7.17) pg/mL at baseline to 4.28 (3.38–7.5) pg/mL  at 3 months and to 4.78 (3.4–7.01) pg/mL  after 6 months of PD in patients with preserved LV function compared to TNF-α drop from 4.79 (2.94–6.53) pg/mL at baseline to 4.29 (2.48–5.51) pg/mL  at 3 months and to 3.91 (2.52–6.26) pg/mL  after 6 months in patients with low LV function. Circulating level of IL-6 decreased from median of 15.83 (9.11–27.83) pg/mL at baseline to 9.98 (8.58–13.13) pg/mL  at 3 months and to 8.75 (2.22–17.55) pg/mL  after 6 months of PD in patients with preserved LV function compared to IL-6 drop from 28.55 (5.74–52.46) pg/mL at baseline to 6.49 (3.34–43.29) pg/mL  at 3 months and to 14.6 (3.3–24.43) pg/mL  after 6 months in patients with low LV function. In patients with preserved LV function, the cause of CHF was nonischemic. Two patients had diastolic heart failure, one patient had restrictive cardiomyopathy with severe pulmonary hypertension of unknown cause, and one had primary pulmonary hypertension with right heart failure.Inside the subgroups of patients, it was found that circulating TNF-P = 0.1323; n = 5) at 3 months and was 16.95 (2.22–21.56) pg/mL  after 6 months of PD in patients with preserved RV function compared to IL-6 fall from 28.19 (11.6–52.46) pg/mL at baseline to 9.56 (5.02–26.42) pg/mL  at 3 months and to 8.75 (4.87–24.43) pg/mL  after 6 months in patients with decreased RV function.In patients with preserved RV function, circulating IL-6 levels decreased insignificantly following PD treatment from median of 13.4 (5.74–52.46) pg/mL at baseline to 8.58 (3.34–43.29) pg/mL  pg/mL at baseline to 4.29 (2.48–5.51) pg/mL  at 3 months and to 3.98 (2.59–6.26) pg/mL  after 6 months of PD in patients treated with ACE-I or ARBs compared to TNF-α drop from 4.8 (3.24–7.17) pg/mL at baseline to 4.28 (3.25–7.5) pg/mL  at 3 months and to 4.12 (2.52–7.01) pg/mL  after 6 months in patients without ACE-I or ARBs. Circulating level of IL-6 decreased from median of 28.55 (11.6–52.46) pg/mL at baseline to 6.49 (5.02–26.42) pg/mL  at 3 months and to 11.35 (4.87–24.43) pg/mL  after 6 months of PD in patients treated with ACE-I or ARBs compared to IL-6 drop from 16.44 (5.74–52.46) pg/mL at baseline to 9.56 (3.34–43.29) pg/mL  at 3 months and to 12.85 (2.22–21.56) pg/mL  after 6 months in patients without ACE-I or ARBs.Circulating TNF-α level decreased from median of 4.87 (2.94–5.43) pg/mL at baseline to 3.49 (2.48–4.29) pg/mL  at 3 months and to 3.54 (2.59–3.91) pg/mL  after 6 months of PD in patients treated with spironolactone compared to TNF-α drop from 4.79 (3.24–7.17) pg/mL at baseline to 4.78 (3.3–7.5) pg/mL  at 3 months and to 4.26 (2.52–7.01) pg/mL  after 6 months in patients without spironolactone. Circulating level of IL-6 decreased from median of 26.61 (5.74–52.46) pg/mL at baseline to 6.26 (4.61–26.42) pg/mL  at 3 months and to 8.1 (3.3–24.43) pg/mL  after 6 months of PD in patients treated with spironolactone compared to IL-6 drop from 18.25 (9.11–52.46) pg/mL at baseline to 9.58 (3.34–43.29) pg/mL  at 3 months and to 14.6 (2.22–21.56) pg/mL  after 6 months in patients without spironolactone.Circulating TNF-β-blockers lower natriuretic peptide values [Our study confirmed that PD treatment effectively removes fluid overload in patients with refractory CHF. Brain natriuretic peptide (BNP) levels measured 18-fold normal before the treatment, decreased significantly after 3 months of treatment, and remained stable at 6 months. Secretion of natriuretic peptides, BNP and amino-terminal pro-B-type natriuretic peptide (NTpro-BNP), is stimulated by ventricular stretch and wall tension in CHF. Both BNP and NT-pro-BNP plasma concentration have been shown to be useful in the diagnosis  and riske values . PatientCRP is liver-derived protein that is regulated by interleukin-6 . CRP hasβ-adrenergic receptors, induction of apoptosis, and stimulation of genes involved in myocardial remodeling [α and IL-6 circulating levels are elevated and correlate with disease severity in heart failure . Proinfiewed in , 34. Ciriewed in . Most stiewed in .β-adrenergic blockade has also been shown to result in significant reductions in proinflammatory cytokine levels in clinical studies with HF patients [α and IL-6 levels showing additional benefit to already maximally tolerate traditional drug regiments. The interesting finding was an insignificant effect of PD treatment on TNF and IL-6 levels in patients with preserved LV function and on IL-6 level in patients with preserved RV function. This result needs further confirmation on large sample size. Larger patient's group size is also needed to separate the effect of PD on inflammatory cytokines from the effects of such standard drugs as ACE-I, previously shown to reduce circulating proinflammatory cytokines [Clinical studies have shown that treatment with angiotensin receptor antagonists can lead to significant reductions in circulating levels of TNF in patients with HF . β-adrenpatients –44. Treapatients . Other spatients . Our finytokines .β1 and inadequately raised levels of IL-10 in relation to the elevated TNF concentrations, and these abnormalities in the cytokine network were most pronounced in patients with the most severe HF [α levels in patients with dilated cardiomyopathy and may support the concept that the increase of IL-10 levels enhances the release of sTNFR2 [α levels, due to beta-blocker therapy [α reduction.The proinflammatory cytokine response is controlled by a series of immunoregulatory molecules, termed the “anti-inflammatory” cytokines. These cytokines act in concert with specific cytokine inhibitors and soluble cytokine receptors to regulate the human immune response. Their physiologic role in inflammation and pathologic role in HF are being increasingly recognized . In seveevere HF . Althougevere HF , in patievere HF . Therefoevere HF , 50. It f sTNFR2 . Moreove therapy . Therefo therapy . We demoWe do not think that removal of proinflammatory cytokines by peritoneal membrane had a significant impact on cytokine plasma levels. Most of our patients were treated with one or two dialysis exchanges per day; therefore, significant removal is unlikely. It was also demonstrated that clearances of high molecular weight compounds such as b2-microglobulin by PD are significantly lower as compared to the clearances of the uremic retention solutes urea nitrogen and creatinine because high molecular weight hampers their diffusive and convective transport through the pores of the peritoneal membrane . It was α and IL-6 in patients with refractory CHF and fluid overload showing additional benefit to already maximally tolerated traditional drug regiments. The limitations of the present study include its small number of patients and the lack of control group. In this regard, we cannot rule out that the observed decrease in inflammatory biomarkers was due to regression to the mean, more careful clinical follow-up compared with routine standards of care, or Hawthorne's effect rather than PD for itself.We assume that PD treatment can lower the circulating level of proinflammatory TNF-In this group of advanced CHF patients refractory to traditional drug therapy with extremely high BNP levels, the effect of PD treatment on circulating IL-6 was the most prominent finding. In this regard, IL-6 can serve as biomarker to guide therapy in those patients. It appears that CRP in which liver production is regulated by IL-6 could also be used as a reliable marker for therapy response, taking into account the fact that its role in pathogenesis and progression of HF is less clear. Large-scale trials are needed to check whether the changes in inflammatory biomarkers over time correlate with morbidity and mortality in HF patients.


Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organization (WHO) for HIV-1-infected individuals in settings with high infectious disease prevalence. The WHO 2006 guidelines were developed prior to the scale-up of antiretroviral therapy (ART). The threshold for CTX discontinuation following ART is undefined in resource-limited settings.3 in a malaria-endemic region in Kenya. Participants were randomized and followed up at 3-mo intervals for 12 mo. The primary endpoint was a composite of morbidity  and mortality. Incidence rate ratios (IRRs) were estimated using Poisson regression.Between 1 February 2012 and 30 September 2013, we conducted an unblinded non-inferiority randomized controlled trial of CTX prophylaxis cessation versus continuation among HIV-1-infected adults on ART for ≥18 mo with CD4 count > 350 cells/mmp < 0.001), driven by malaria morbidity. There were 34 cases of malaria, with 33 in the CTX discontinuation arm . Diarrhea and pneumonia rates did not differ significantly between arms . Study limitations include a lack of placebo and a lower incidence of morbidity events than expected.Among 538 ART-treated adults screened, 500 were enrolled and randomized, 250 per arm. Median age was 40 y, 361 (72%) were women, and 442 (88%) reported insecticide-treated bednet use. Combined morbidity/mortality was significantly higher in the CTX discontinuation arm  are currently infected with HIV, the virus that causes AIDS. HIV, which is usually transmitted through unprotected sex with an infected individual, gradually destroys CD4 lymphocytes and other immune system cells. Because destruction of the immune system leaves HIV-infected individuals susceptible to “opportunistic” infections, early in the AIDS epidemic, most HIV-positive individuals died within ten years of infection. In 1996, effective antiretroviral therapy (ART)—drug regimens that stop HIV replicating and allow the immune system to recover its ability to fight infections—became available. For people living in affluent countries, HIV/AIDS became a chronic condition, but because ART was expensive, HIV/AIDS remained fatal in resource-limited countries. In 2003, the international community began to work towards achieving universal access to ART. Now, at least a third of people living with HIV have access to ART, and the global mortality (death) rate from HIV/AIDS is falling.3 blood should take CTX and that, in settings with a high prevalence of HIV infection and limited health infrastructure, all HIV-infected adults should take CTX. However, these guidelines were developed before access to ART was scaled-up, and CTX prophylaxis has risks  as well as benefits. In this unblinded non-inferiority randomized controlled trial, the researchers investigate the effects of CTX discontinuation among ART-treated HIV-infected adults in Kenya. A randomized controlled trial compares the outcomes of individuals randomly assigned to different treatments; in an unblinded trial, everyone involved in the trial knows who is taking which treatment; a non-inferiority trial investigates whether one treatment is not worse than another treatment.To prevent opportunistic infections, the World Health Organization (WHO) recommends cotrimoxazole (CTX) prophylaxis for HIV-infected individuals. CTX is a combination of two antimicrobial drugs that is active against a range of bacterial, fungal, and parasitic infections; prophylactic antimicrobials are taken to prevent infection. CTX decreases morbidity (illness) and mortality among HIV-infected individuals primarily by reducing the rates of malaria, pneumonia, diarrhea, and severe bacterial infections. The 2006 WHO guidelines for CTX prophylaxis recommend that, in resource-limited countries, HIV-infected patients whose CD4 count is ≤350 cells/mm3, and who were taking CTX. Half the participants continued to take CTX; the remainder stopped taking CTX. After 12 months of follow-up, the combined rate of morbidity  and mortality was significantly higher in the CTX discontinuation arm than in the CTX continuation arm (a significant difference is one that is unlikely to have happened by chance). The difference in this primary outcome between the trial arms was driven by malaria morbidity—there were 33 cases of malaria in the CTX discontinuation arm but only one case in the CTX continuation arm. By contrast, the rates of pneumonia and diarrhea did not differ significantly between the trial arms.The researchers enrolled 500 HIV-infected adults living in a malaria-endemic region of Kenya  who had been treated with ART for ≥18 months, who had a CD4 count of >350 cells/mmBecause the difference between the two trial arms in terms of the primary endpoint was greater than the researchers’ predefined non-inferiority limit, these findings suggest that CTX discontinuation is inferior to CTX continuation among ART-treated, immune-reconstituted HIV-infected adults living in a malaria-endemic region. The accuracy of these findings may be affected by the lack of blinding—the clinicians’ care decisions and the patients’ threshold for seeking care may have been influenced by their knowledge of their trial arm assignment. Overall, however, these findings suggest that malaria endemicity should be considered when making decisions about whether to stop CTX after ART-driven immune reconstitution. Indeed, in December 2014, following the release of preliminary data from this trial and the completion of an independent trial on CTX discontinuation, WHO issued supplemental guidelines on CTX prophylaxis. These state that CTX prophylaxis can be discontinued for HIV-infected adults who are clinically stable on ART and have evidence of immune recovery and viral suppression but recommend that CTX prophylaxis be continued regardless of CD4 cell count or HIV/AIDS clinical stage in settings where malaria is endemic and/or severe bacterial infections are common.http://dx.doi.org/10.1371/journal.pmed.1001934.This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at HIV infection and AIDSInformation is available from the US National Institute of Allergy and Infectious Diseases on NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, information on opportunistic infections and on CTX prophylaxis, and personal stories about living with HIV/AIDSAvert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV/AIDS in Kenya, on ART, and on opportunistic infections and CTX prophylaxis: Avert also provides personal stories about living with HIV/AIDSInformation is available from HIV/AIDS, including its 2013 guidelines on using ART to treat HIV infection and its December 2014 supplement to these guidelines, which contains updated recommendations on CTX prophylaxis; a factsheet about CTX prophylaxis is also availableWHO provides information on all aspects of 2015 World AIDS Day Report provides up-to-date information about the AIDS epidemic, including progress towards universal access to ARTThe this trial is availableMore information about  Cotrimoxazole (CTX), fixed-dose trimethoprim-sulfamethoxazole, is a low-cost and widely utilized broad spectrum antibiotic used to prevent opportunistic infections in patients with human immunodeficiency virus type 1 (HIV-1). Prophylaxis with CTX has been shown to decrease mortality, morbidity, and hospitalizations among HIV-infected adults  and chil3) to prevent Pneumocystis jiroveci pneumonia and toxoplasmosis [3) [Recommendations for CTX use in adults with HIV-1 vary by setting. In the United States and Europe, CTX is recommended for HIV-1-infected adults with severe immunosuppression (CD4 count < 200 cells/mmlasmosis –14. Follosis [3) ,15–17.3 [In resource-limited countries, the threshold for CTX discontinuation following ART remains undefined. The 2006 World Health Organization (WHO) guidelines recommend CTX prophylaxis for HIV-1-infected patients with a CD4 cell count of ≤350 cells/mm3 . For set3 . HoweverAt the time of our protocol submission, there were no randomized trial data on the effects of discontinuing CTX following ART in resource-limited settings. However, prior to study initiation, a randomized controlled trial (RCT) conducted in Uganda demonstrated an increased incidence of malaria and diarrhea among ART-treated adults who discontinued CTX compared to those who continued . In this3) to determine whether discontinuation of CTX was non-inferior to continued CTX prophylaxis in decreasing morbidity. Following completion of our RCT, the WHO published supplemental guidelines on the use of CTX [We conducted an RCT among adults on ART with evidence of immune recovery , and individuals in the CTX discontinuation arm discontinued CTX at the time of enrollment. The primary aim of the trial was to determine whether CTX prophylaxis can be discontinued in ART-treated, immune-reconstituted adults without significant harm.3). Additionally, participants had to be currently taking CTX for HIV and willing to return to the clinic every 3 mo for the 12-mo study follow-up period. We excluded individuals who were pregnant or breastfeeding, who were taking second-line ARVs, or who had a documented allergy to CTX.We recruited HIV-infected individuals between February 1, 2012, and August 27, 2012, at the HIV Treatment and Care Clinic, known as the Patient Support Center (PSC), of Homa Bay District Hospital in western Kenya. Individuals were eligible for the study if they were ≥18 y old, HIV seropositive, and taking first-line antiretrovirals (ARVs) with evidence of immune recovery  to either the CTX continuation or CTX discontinuation arm. Each participant’s arm allocation was concealed from study investigators, staff, and participants in a randomization envelope until the end of the enrollment visit, when the envelope was opened; participants and study staff were not masked to treatment assignment thereafter.A history and physical examination was conducted at randomization and at 3-mo intervals during follow-up. At randomization, 6 mo, and 12 mo, specimens were obtained for a complete blood count with CD4 count per Kenyan guidelines . If clinParticipants were encouraged to come to the clinic to see study providers for any illness as a sick visit. Sick visits included more intensive workup, with malaria rapid diagnostic test, thick/thin blood smears, and measurement of alanine aminotransferase level and HIV-1 RNA viral load, as clinically indicated and available. Moreover, participants were contacted every 2 wk by study counselors using text messaging or phone calls and asked about recent illness and compliance with study arm protocol. Any participant reporting any symptoms was asked to return to the clinic for evaluation by study staff. To decrease the risk of malaria and diarrhea in this cohort, we provided insecticide-treated bednets and water filters to all participants.At the completion of the study, participants were transferred back to PSC care providers. Those who had stopped CTX were counseled on restarting CTX again as per Kenyan guidelines .The primary morbidity/mortality endpoint was a composite of malaria, pneumonia, and diarrhea events and non-trauma mortality events. Malaria was defined as a fever, measured or self-reported, and either a positive rapid diagnostic test or thick smear showing the presence of parasites. Pneumonia was defined as fever, cough, or tachypnea and either a clinically abnormal chest examination or evidence of infiltrate on chest radiograph significant enough to require hospitalization. Diarrhea was defined as a self-report of three or more loose stools in a 24-h period in the past week. An independent clinician  who was blind to arm assignment at the time of adjudication evaluated all serious adverse events (SAEs) and designated their likelihood of being research-related. Each event was deemed potentially related to the research if it could have been due to either CTX use or CTX discontinuation.Prespecified secondary endpoints were 12-mo CD4 change and ART treatment failure. Treatment failure was defined by Kenya National AIDS & STI Control Programme guidelines and was categorized as clinical, immunologic, or virologic . VirologWe estimated the needed sample size for the comparison of interest: the incidence rate ratio (IRR) comparing the rate of morbidity/mortality observed in the CTX discontinuation arm to the rate observed in the CTX continuation arm. We chose a non-inferiority limit of 1.25, thus planning to conclude non-inferiority of CTX discontinuation if the upper bound of the two-sided 90% confidence interval (CI) for the IRR was less than 1.25 . We usedFor analysis of the primary endpoint, we calculated a combined morbidity/mortality incidence rate for each treatment arm. We used Poisson regression with robust error variance to estimate the IRR, using the natural logarithm of follow-up time as an offset variable. We conducted both intention-to-treat (ITT) and per-protocol (PP) analyses. ITT analyses assigned all follow-up time from a participant to that participant’s original randomization arm. In contrast, PP analyses reflected changes to CTX regimen. Specifically, for participants randomized to discontinue CTX who restarted CTX due to pregnancy, PP analyses excluded person-time following the restart of CTX.3, >600 cells/mm3) and duration of ART at enrollment . We also calculated IRRs for the rate of SAEs and the rate of all grade 2 or higher AEs. To estimate IRRs, we used Poisson regression as described above or exact Poisson regression where appropriate. We compared 12-mo change in CD4 count in the two groups using a linear mixed effects model that included main effects for arm, time, and a time–treatment arm interaction. This model used CD4 data collected at the scheduled enrollment, month 6, and month 12 study visits. We used Cox proportional hazards regression to compare time to ART treatment failure between arms.In secondary analyses, we calculated IRRs comparing the CTX discontinuation arm to the continuation arm for each individual component of the morbidity/mortality outcome, as well as for subgroups defined by enrollment CD4 count (≤600 cells/mmAn independent data safety and monitoring board (DSMB) was convened four times during the course of the study to review study procedures, participant retention, and safety data by arm and included review of any relevant new data. The DSMB adopted a safety stopping rule based on SAEs deemed potentially research-related (due to either discontinuing CTX or continuing CTX) by the DSMB safety monitor, who would be blind to arm assignment at the time of adjudication. Non-severe  malaria, pneumonia, and diarrhea events were not included as criteria for early stopping, based on the rationale that rates of non-severe AEs in the CTX discontinuation arm may reflect rates in HIV-uninfected community members and could be offset by non-severe AEs related to CTX use. The interim safety analysis was conducted in accordance with the Lan–DeMets implementation of the O’Brien–Fleming boundary for harm; the alpha spending function was based on an information fraction equal to the interim number of events in all arms divided by the total number of expected events by the conclusion of the study. The interim analysis was conducted at an information fraction of 0.64, and the study stopping criterion was not met.We used Stata version 12.1  for all 3, and median ART duration was 4.5 y. Randomization resulted in baseline characteristics that were generally well-balanced between the two arms  participants randomized to the CTX discontinuation arm had restarted CTX due to pregnancy.p < 0.001), we could not conclude non-inferiority of CTX discontinuation. The difference by arm was largely driven by the malaria component: the rate of malaria was 0.4 per 100 person-years in the CTX continuation arm and 13.0 per 100 person-years in the CTX discontinuation arm . PP results were similar to ITT results, with an IRR of 2.27 (95% CI 1.52–3.39) for the composite endpoint of morbidity and mortality and an IRR of 33.56 (95% CI 4.60–245.01) for malaria. Among individuals in the CTX discontinuation arm, malaria cases occurred throughout the study follow-up period, without evidence of an early “rebound”  in the subgroup with CD4 count > 600 cells/mm3 .In subgroup analyses Tables  and 4, mReported bednet use at enrollment was high, at 88%. Reported bednet use during follow-up was high (96.4%) and was similar between both arms.n = 108), non-malaria febrile or flu-like illness (n = 53), upper respiratory tract infection (n = 49), diarrhea (n = 38), and malaria (n = 34). Anemia was more frequent in the CTX discontinuation arm: there were 42 anemia events in the CTX continuation arm and 66 anemia events in the CTX discontinuation arm. The rates were 16.6 per 100 person-years in the CTX continuation arm and 26.1 per 100 person-years in the CTX discontinuation arm, a statistically significant difference . There were no hypersensitivity reactions.There were 34 SAEs, of which 27 were grade 3 or higher AEs (including one death), and 18 were deemed potentially related to the research (five in the CTX continuation arm and 13 in the CTX discontinuation arm) . The ratp < 0.001).The estimated rate of grade 2 or higher AEs was 63.5 per 100 person-years in the CTX continuation arm and 99.5 per 100 person-years in the CTX discontinuation arm, a statistically significant difference  in the CTX continuation arm and of 31.6 cells/mm3/y (95% CI 10.7–52.6) in the CTX discontinuation arm (p = 0.85).Analyses of 12-mo CD4 change included CD4 counts at enrollment, at month 6, and at month 12 for all participants contributing data at these time points. There was an increase in CD4 count of 28.8 cells/mmtion arm . There wp = 0.73).There were a total of nine ART treatment failure events: six immunologic treatment failures, two virologic treatment failures, and one clinical treatment failure. Five ART treatment failure events were in the CTX continuation arm, and four were in the CTX discontinuation arm. There was no statistically significant difference between arms in time to treatment failure .Only one other randomized control trial to date has examined CTX discontinuation after ART initiation in adults in a resource-limited setting . A recenData from this study were presented at the Conference on Retroviruses and Opportunistic Infections in 2014  and subsThe prior CTX discontinuation study in Uganda was stopped early after the researchers observed increased malaria, and therefore it had a limited follow-up time of up to 4 mo . It is pIn contrast to other CTX discontinuation studies, we did not observe an increase in diarrhea in participants in the CTX discontinuation arm ,10. OverThis study complements findings by Walker et al. , who notOur study demonstrated low rates of treatment-limiting AEs such as hematological AEs, rash, or hypersensitivity among participants who continued CTX. All participants were on CTX at the study start, therefore likely limiting the group of participants who would have reactions to the antimicrobial and suffer from adverse effects. AEs were significantly more common among those who stopped CTX, consistent with prior studies ,6,10,11.3 in both arms and had been on ART for a median of over 4 y with few prior hospitalizations in the past 3 mo. This, coupled with high retention, suggests that these patients may represent an elite subgroup of patients who took advantage of a strong PSC.Our study had several strengths and limitations. Because our study was an unblinded clinical trial without a placebo, clinician’s care decisions, as well as the patients’ threshold to come in for care, may have been influenced by trial arm. A second limitation, for statistical analyses, was an observed incidence of morbidity events that was lower than expected. Additionally, our study was limited to 12 mo of follow-up. A strength of the study was high retention (98% in each arm). The PSC at the Homa Bay District Hospital had a long history of collaboration with Médecins Sans Frontières and a reputation for excellent care, which contributed to retention in the trial. Participants had median CD4 counts approaching 600 cells/mmIn conclusion, CTX discontinuation among ART-treated adults in a region with endemic malaria results in increased incidence of clinical malaria but not pneumonia or diarrhea. The implications are broad, and our results suggest that CTX prophylaxis should continue in regions with endemic malaria. However, in regions without malaria or with less endemicity, CTX cessation may be possible after immune recovery.S1 Table(DOCX)Click here for additional data file.S1 Text(PDF)Click here for additional data file.S2 Text(DOC)Click here for additional data file.S3 Text(DOCX)Click here for additional data file.


World-wide, the notable expansion of HIV/AIDS treatment programs in resource-limited settings has lead to an increasing number of patients in need of second-line cART. To adequately address and prepare for this scenario, critical assessments of the outcomes of second-line cART are particularly relevant in settings where monitoring strategies may be inadequate. We evaluated virologic outcomes of second-line combination antiretroviral therapy (cART) among HIV-infected individuals from Brazil.This study was conducted at the Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, at Rio de Janeiro, Brazio. For this study we included all patients who started first-line and second-line cART between 2000 and 2013. Second-line cART required a switch in the anchor drug of first-line cART. We evaluated time from second-line start to virologic failure and factors associated with increased risk of failure using multivariable Cox proportional hazards regression models.3 (IQR: 240-617)] compared to those starting second-line cART after documented virologic failure [230 cells/mm3 (IQR: 118-322.5)] (p < 0.01). Median time from second-line cART initiation to failure was also significantly different for patients starting second-line cART undetectable compared to those who with documented virologic failure (log-rank test p < 0.01). Multivariable Cox models showed that younger age, lower education, and HIV RNA level were independently associated with an increased hazard of second-line failure among those with documented virologic failure at start of second-line cART.Among the 1,311 patients who started first-line cART a total of 386 patients (29.5%) initiated second-line cART, out of which 35.0% and 60.6% switched from their first-line to their second-line cART when their HIV RNA was undetectable and after documented virologic failure, respectively. At second line cART initiation, median age was 38 years [interquartile range (IQR): 31-45years]. Median CD4 count was significantly different for patients starting second-line cART undetectable [412 cells/mmWe have shown that in a middle-income country with universal access to cART, having a detectable HIV RNA at the start of second-line cART as well as younger age and lower education negatively impact second-line outcomes. Our findings could guide HIV treatment efforts as to which strategies would help maximize the durability of these regimens.The online version of this article (doi:10.1186/s12879-014-0699-5) contains supplementary material, which is available to authorized users. Globally, studies addressing second-line combination antiretroviral (cART) virologic, immunologic and clinical outcomes have become increasingly common in recent years –5]. Res. Res5]. Second-line cART accounts for less than 5% of total antiretroviral treatments in resource-limited settings . In LatiThis study was conducted at the Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz , where care has been provided to HIV/AIDS patients since 1986. INI is one of the largest infectious diseases research centers in Brazil, where over five thousand HIV infected patients have been treated since the beginning of the AIDS epidemic. An observational, longitudinal, clinical database is maintained on patients receiving primary and specialized HIV care at the clinic. Details and results of the HIV/AIDS Clinical Cohort can be found elsewhere . INI’s IFor this study we included all patients who started first-line cART between January 01, 2000 and June 30, 2010. Follow-up information included data up to December 30, 2013. Included patients had to be at least 18 years old at cohort enrollment and have followed first-line cART by a second-line cART regimen. First- and second-line cART regimens were defined as two or more nucleoside reverse transcriptase inhibitors (NRTI) plus an anchor drug . Patients were treated according to the Brazilian HIV Treatment Guidelines that recommend as a preferred first-line cART a regimen based on NNRTIs though PI-based regimens can also be prescribed. In contrast, second-line cART, according to the guideline, should be PI-based though NNRTI-based regimens can also alternatively be prescribed  compared to those starting second-line cART after documented virologic failure [230 cells/mm3 (IQR: 118-322.5)] .At second line cART initiation, median age was 38 years [interquartile range (IQR): 31-45years], 59% were male and half were non-white (Table Most anchor drug switches were either a modification from NNRTI- or PI-based regimens to a boosted PI-based regimen (73%) and to a much smaller extent from a PI/PI-r to an NNRTI 19%). Overall, 296 patients (82%) used a PI-based second-line cART out of which the majority  used a ritonavir-boosted PI (PI-r). Lopinavir/r was used by 46% (135/296) and ATV/r by 37% (111/296). The most frequently used NRTI backbones were: AZT/3TC  and 3TC/TDF or FTC/TDF . For patients initiating second-line cART with an undetectable HIV RNA, the most frequent switches were from NNRTI-based to a boosted PI-based cART (37%) followed by PI/PI-r to NNRTI-based (31%) and PI/PI-r to PI/PI-r (22%). For patients who initiated second-line cART with a detectable HIV RNA, the most frequent modification was from NNRTI to a boosted PI-based (65%) cART . For patients who initiated second-line cART with an undetectable HIV RNA, the median time was 20.3 months (95% 16.7-24.2) and for those who initiated cART with a detectable HIV RNA, the median time was 20.8 months (18.4-23.1). The Kaplan-Meier plot of the time from first-line cART to second-line cART is given in Figure Among the 386 patients who started second-line cART (median follow-up time of 1.9 years), 199 patients developed virologic failure, 174 were censored, and 13 patients died during follow-up due to AIDS-related causes (5 and 6 deaths in the undetectable and detectable groups). The overall incidence of second-line failure was 12/1000 person-years (95% CI 10-14/1000 person-years). The incidence of second-line failure was 5.7/1000 person-years (95% CI 4.2-7.7/1000 person-years) and 19/1000 person-years (95% CI 16-23/1000 person-years) among those who started second line cART with an undetectable and a detectable HIV RNA . The overall probability of failure at 12, 24 and 36 months was 26%, 41% and 48% respectively. For the undetectable group, 12-, 24- and 36-months probability of failure was 15%, 23% and 30% while for the detectable group, 12-, 24- and 36-months probability of failure was 34%, 55% and 62%.Overall, the median time from second-line cART to virologic failure was 40.0 months 95% CI 30.4, 52.2). The median time from second-line cART initiation to failure was significantly different between the two groups  for second-line failure stratified by HIV RNA level at second-line cART initiation (detectable and undetectable) are shown in Table For patients who initiated second-line cART with a detectable HIV RNA, age and level of education were independently associated with the hazard of second-line failure. Again, a protective pattern was found for older age when compared to younger individuals and for higher education when compared to those with less years of education Table . Whilst HIV genotyping results at first-line cART failure were available for 39% (91/234) of the patients who started second-line cART with a detectable viral load. A genotyping result yielding wild type virus was found in 7.7% (7/91) of patients. Overall, M184V was the most prevalent mutation . K65R was identified in 38% of the patients using TDF (8/21) all of which were using an NNRTI based cART regimen. At least one primary PI mutation was found for 75% (6/8) and 55% (5/9) of patients using PI and PI-r cART based regimens. Among those patients using a NNRTI based regimen, the most prevalent NNRTI mutation was K103N .Resistance testing results were available for 23% (43/187) of the patients at second-line cART virologic failure. Overall, 32.5% (14/43) of the genotyping results yielded no resistance mutations (wild type virus), and this was higher among those patients using a boosted PI cART regimen . More than 3 TAMS were identified in 11.6% (5/43). At least one primary PI mutation was identified in 75% (3/4) of patients using an unboosted PI cART based regimen , and 10% (3/30) among those using a PI-r cART regimen .Our results show that more than half of our study population (60%) started second-line cART after a documented virologic failure, and that the outcomes from start of second-line cART were significantly different for patients who started second-line cART with an undetectable compared to a detectable HIV RNA. The median time from second-line cART to failure was significantly higher for those who started with an undetectable HIV RNA compared to those with a detectable HIV RNA. In addition, the incidence of second-line failure was 3.4 times higher for those with a detectable viral load and the probabilities of failure at 12, 24 and 36 months were consistently higher for this group. Taken together, these results clearly point to differences in outcomes as a function of an individual’s HIV RNA at start of second-line cART which is in agreement with the findings from a multicenter study with a similar design .Given that an undetectable HIV RNA can be taken as surrogate marker for treatment response and possibly good adherence and no viral resistance, it was expected that patients starting second-line cART undetectable would show improved outcomes. Indeed, non-adherence to therapy has been shown to be one of the strongest predictors of cART failure ,22]. In. In22]. As for socio-demographic factors impacting second-line cART outcomes, our results suggest that older age and higher education were associated with a decreased hazard of failure. For this sample population, age older than 30 years at start of second-line cART significantly decreased the hazard of failure among patients with detectable and undetectable HIV RNA at second-line cART start. In a recent analysis of first-line cART conducted by our group, both factors were also found to impact treatment effectiveness  and a hiOur results also show that anchor drug switches from first-line to second-line cART can impact the hazard of second-line cART among patients who had an undetectable HIV RNA at the start of second-line cART. We found that patients switching from an NNRTI-based regimen to an unboosted PI-based regimen had increased hazard of failure of second-line cART when compared to those switching to a boosted-PI-based regimen. In contrast, patients were protected from failure if switches were from unboosted or boosted PI-based regimens to either NNRTI-based regimens or a boosted PI-based regimen. These results echo current knowledge since unboosted PI regimens are no longer an option in contemporary treatment guidelines ,18]. Ou. Ou18]. Another finding from our study is that the median time from first-line to second-line cART was not significantly different among those who started second-line cART undetectable compared to those who started with a detectable HIV RNA, suggesting that concurrent reasons to switch first-line cART occurred overtime which included toxicities in addition to virologic failure. In fact, a higher proportion of patients who switched to second-line cART while having HIV RNA undetectable did so due to toxicities . A somewhat surprising finding was that the median time from second-line cART to failure was significantly longer than that of first-line cART (40 months for second-line compared to 20 months for first-line). This may result from a high proportion of first-line cART switches due to toxicities. In previous analyses we have shown that toxicities were the driving force for first-line cART modifications and/or interruptions which were highly incident in our cohort especially during the first year of cART .Although HIV genotyping tests are available in Brazil through the Public Health System since 2001, only 39% of the patients had a resistance test performed after first-line virologic failure and before starting second-line cART. Also, a small number of patients (23%) who developed second-line cART virologic failure had a resistance testing performed at second-line failure. Several issues such as insufficient laboratory infrastructure, long intervals to receive the genotyping results, technical limitations related to the viral load threshold for viral amplification , among others, may explain the small number of tests performed. Of note, although our numbers are very small, it is important to highlight the number of genotyping results yielding wild type virus among patients using a PI-r cART regimen at second-line virologic failure. Although boosted PI cART regimens have a higher genetic barrier against resistance ,34], it, it34], Our study has strengths and limitations. A major strength of our study is its large time span, covering 13 years of cART, in a cohort of HIV-infected patients from a middle-income country that provides universal access to treatment. In this scenario we were able to study outcomes of second-line cART with detailed socio-demographic, laboratory and treatment data. To the best of our knowledge, this is the first study of second-line cART outcomes in Brazil and, in the international literature, possibly one of the few studies that longitudinally evaluated outcomes of second-line cART. Lack of adherence data is a major limitation of our study. Despite this pitfall, given the availability of HIV RNA measurements, we were capable of using an undetectable HIV RNA as a proxy for treatment adherence which allowed us to discuss important findings with respect to second-line cART. That said, specific treatment adherence measures are needed to study its impact as well as to allow for adherence interventions to be carried out. Current WHO guidelines recommend that patients presenting with failure should be subject to adherence support interventions, after which a second viral load test should be performed prior to deciding on a regimen switch . In thisAchieving sustained viral suppression is the objective of any cART irrespective if it is the first-line or subsequent treatment regimens. The need for lifelong antiretroviral therapy for HIV infection argues for the use of subsequent regimens with the most favorable efficacy and safety profile, ideally including drug classes without super-imposable resistance patterns. We have shown that in a middle-income country with universal access to cART, having a detectable HIV RNA at the start of second-line cART negatively impacts second-line outcomes and that factors such as younger age and lower education can also negatively impact second-line cART outcomes. Although third-line cARTs such as darunavir, etravirine, raltegravir and maraviroc are available in Brazil, the costs associated with these drugs are significantly higher, and treatment regimens frequently include a larger number of pills, adding further complexity to treatment management. As such, tailored interventions to the specific populations here described are critical to guarantee the benefits of second-line cART.


For some patients, it remains a challenge to achieve complete virological suppression which is the goal of antiretroviral therapy (ART). Identifying factors associated with low-level viraemia (LLV) and virological failure (VF) under ART might help to optimize management of these patients.We investigated patients from the Austrian HIV Cohort Study receiving unmodified ART for >6 months with two nucleoside reverse-transcriptase inhibitors (NRTIs) with either a non-nucleoside reverse-transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) or an integrase inhibitor (INSTI) between 1 July 2012 and 1 July 2013 with at least one viral load (VL) measurement below the limit of detection (BLD) or below level of quantification (BLQ) in their treatment history. VF was defined as HIV-RNA levels ≥200 copies/mL and all other quantifiable measurements were classified as LLV. Factors associated with LLV and VF compared to BLD and BLQ were identified by using logistic regression models.Of the 2,276 patients analyzed, 1,972 (86.6%) were BLD or BLQ, 222 (9.8%) showed LLV and 82 (3.6%) had VF. A higher risk for LLV and VF was found in patients with ART interruptions and in patients with boosted PI therapy. The risk for LLV and VF was lower in patients from a centre which uses Abbott RealTime HIV-1 assay compared to the other centres measuring VL by the Roche Cobas AmpliPrep/Cobas TaqMan 2.0. A higher risk for LLV but not for VF was found in patients with a higher VL before ART and shorter ART duration. A higher risk for VF but not for LLV was found in patients of younger age, originating from a high prevalence country, with a lower CD4 count and in male injecting drug users.This study of well-defined patients on stable ART over a period of more than six months gives insights into the different factors associated with LLV and VF. In patients with VF, factors associated with adherence play a prominent role, whereas in patients with LLV, the biology of viral replication comes additionally into effect. Despite its observational design, it has implications for patient management and forms the basis for future outcome studies.