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Antiretroviral agents active against drug-resistant HIV-1 are needed for treatment-experienced patients. The aim of this trial was to assess the efficacy, safety, and tolerability of TMC125 (etravirine), a non-nucleoside reverse transcriptase inhibitor (NNRTI). DUET-1 is a continuing, multinational randomised, double-blind, placebo-controlled, phase III trial. Treatment-experienced adult patients with virological failure on stable antiretroviral therapy, documented genotypic evidence of NNRTI resistance, viral load over 5000 copies per mL, and three or more primary protease inhibitor mutations were randomly assigned to receive 200 mg TMC125 or placebo twice daily. All patients also received darunavir with low-dose ritonavir and investigator-selected nucleoside reverse transcriptase inhibitors. Enfuvirtide use was optional. The primary endpoint was a confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, with the number NCT00254046. 612 patients were randomised and treated (304 in the TMC125 group, 308 in the placebo group). By week 24, 42 (14%) patients in the TMC125 group and 56 (18%) in the placebo group had discontinued, mainly due to virological failure. At week 24, 170 (56%) patients in the TMC125 group and 119 (39%) patients in the placebo group achieved a confirmed viral load of less than 50 copies per mL (difference in response rates 17%; 95% CI 9–25; p=0·005). Most adverse events were mild or moderate in severity. The type and incidence of adverse events, including neuropsychiatric events, seen with TMC125 were generally comparable with placebo, with the exception of rash (61 [20%] patients on TMC125 vs 30 [10%] on placebo) and diarrhoea (36 [12%] patients on TMC125 vs 63 [20%] on placebo). In treatment-experienced patients with NNRTI resistance, treatment with TMC125 achieved better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.

HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa. In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per μL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per μL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1·18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85–88) in the CDM group and 90% (88–91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4·9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6·94 [95% CI 6·33–7·60] vs 5·24 [4·72–5·81] per 100 person-years; absolute difference 1·70 per 100 person-years [0·87–2·54]; HR 1·31 [1·14–1·51]; p=0·0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1·12 [0·94–1·32]; p=0·19), with anaemia the most common (76 vs 61 cases). ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment. UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

TMC125 (etravirine) is a non-nucleoside reverse-transcriptase inhibitor (NNRTI) with activity against NNRTI-resistant HIV-1 in phase IIb trials. The aim of DUET-2 is to examine the efficacy, tolerability, and safety of TMC125 in treatment-experienced patients. In this continuing randomised, double-blind, placebo-controlled, phase III trial, HIV-1-infected patients on failing antiretroviral therapy with evidence of resistance to currently available NNRTIs and at least three primary protease inhibitor mutations were eligible for enrolment if on stable (8 weeks unchanged) antiretroviral therapy with plasma HIV-1 RNA greater than 5000 copies per mL. Patients were randomly assigned to receive either TMC125 (200 mg) or placebo, each given twice daily with darunavir-ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors, and optional enfuvirtide. The primary endpoint was the proportion of patients with confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00255099. 591 patients were randomised and treated (295 patients in the TMC125 group and 296 in the placebo group). By week 24, 51 (17%) patients in the TMC125 group and 73 (25%) in the placebo group had discontinued, mainly because of virological failure. 183 (62%) patients in the TMC125 group and 129 (44%) in the placebo group achieved confirmed viral load below 50 copies per mL at week 24 (difference 18%, 95% CI 11–26; p=0·0003). The type and frequency of adverse events were much the same in the two groups. In treatment-experienced patients, treatment with TMC125 led to better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.

Structured treatment interruptions of highly-active antiretroviral therapy (HAART) might be particularly relevant for sub-Saharan Africa, where cost-saving strategies could help to increase the number of patients on HAART. We did a randomised trial of structured treatment interruption in Abidjan, Côte d'Ivoire. HIV-infected adults were randomised to receive continuous HAART (CT), CD4-guided HAART (CD4GT) with interruption and reintroduction thresholds at 350 and 250 cells per mm 3, respectively, or 2-months-off, 4-months-on HAART. Primary endpoints were death and severe morbidity (any WHO stage 3 or 4 events and any events leading to death) at month 24. We report data from the CT and CD4GT groups until Oct 31, 2005, when the data safety monitoring board recommended to prematurely stop the CD4GT arm. Analyses were intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00158405. 326 adults (median CD4 count nadir 272 per mm 3) were randomised to the CT or CD4GT groups and followed up for median of 20 months. Incidence of mortality (per 100 person-years) was not different between groups (CT 0·6, CD4GT 1·2; p=0·57). Incidence of severe morbidity (per 100 person-years) was higher in the CDG4T group (17·6) than in the CT group (6·7; p=0·001). The most frequent severe events were invasive bacterial diseases. 79% of severe morbidity episodes occurred in patients with CD4 count 200–500 per mm 3. Patients on CD4GT had severe morbidity rates 2·5-fold higher than those on CT. This difference was mainly due to high rates of common diseases in patients with CD4 count 200–500 per mm 3. This CD4-guided structured treatment interruption strategy should not be recommended in Abidjan.

Background In 2015, the World Health Organization (WHO) launched the Test and Treat policy which supports antiretroviral treatment for all people with HIV, irrespective of CD4 count or clinical stage. This was adopted in 2016 in Nigeria. This policy resulted in scaleup of HIV testing strategies and differentiated models of care including community-based ART. This study evaluated the HIV testing algorithm and assessed the rates of misclassification of HIV status among newly diagnosed clients. Methods Between February and August 2018, whole blood samples were collected from clients newly diagnosed with HIV in Lagos and Benue states. HIV status wasconfirmed with rapid tests using the serial algorithm during outreach sessions for both key populations and general populations. HIV positivity was confirmed using GenScreen™ HIV1/2.O Antibody only ELISA test (BioRad, USA). Optical density (OD) for each sample was measured with the use of Emax microplate reader set at endpoint 450 wavelength. Based on manufacturer’s algorithm, sample OD and calculated cut-off value ratio, an OD < 1.0 was interpreted as negative and > 1.0, positive. Concordance between rapid test algorithm result and ELISA was used to estimate the proportion of samples that were misclassified. Results A total of 788 samples were collected from newly diagnosed clients across 4 sites in Lagos and 3 sites in Benue. Samples were collected from 212 and 178 key populations (KPs) clients in Lagos and Benue, respectively, and from 206 and 192 general population (GPs) clients in Lagos and Benue, respectively. Mean OD was 3.75 (IQR:3.70–3.81) with a standard deviation of 0.13. There was a 100% concordance between rapid test and ELISA results and no misclassification identified. Conclusion We identified no instances of misclassification of positive HIV status suggesting that all clients who have been placed on treatment truly had HIV infection. The 100% concordance rate recorded from all the sites may be attributable to the maturity of the HIV program in Nigerian with a concomitant standard quality assurance system for both clinical and outreach testing services. This finding supports the implementation of the Test and Treat policy that Nigeria has adopted. Scale up of Test and Treat and community ART is thus recommended to increase access to treatment.

Human Immunodeficiency Virus (HIV) is a retrovirus that weakens the immune system, increasing vulnerability to infections and cancers. HIV spreads primarily via sharing needles, from mother to child during childbirth or breastfeeding, or unprotected sexual intercourse. Therefore, early diagnosis and treatment are crucial to prevent the disease progression of HIV to AIDS, which is associated with higher mortality. This study introduces a machine learning-based framework for the classification of HIV infections crucial for preventing the disease’s progression and transmission risk to improve long-term health outcomes. Firstly, the challenges posed by an imbalanced dataset is addressed, using the Synthetic Minority Over-sampling Technique (SMOTE) oversampling technique, which was chosen over two alternative methods based on its superior performance. Additionally, we enhance dataset quality by removing outliers using the interquartile range (IQR) method. A comprehensive two-step feature selection process is employed, resulting in a reduction from 22 original features to 12 critical variables. We evaluate five machine learning models, identifying the Random Forest Classifier (RFC) and Decision Tree Classifier (DTC) as the most effective, as they demonstrate higher classification performance compared to the other models. By integrating these models into a voting classifier, we achieve an overall accuracy of 89%, a precision of 90.84%, a recall of 87.63%, and a F1-score of 98.21%. The model undergoes validation on multiple external datasets with varying instance counts, reinforcing its robustness. Furthermore, an analysis focusing solely on CD4 and CD8 cell counts which are essential lab test data for HIV monitoring, demonstrates an accuracy of 87%, emphasizing the significance of these clinical features for the classification task. Moreover, these outcomes underscore the potential of combining machine learning techniques with critical clinical data to enhance the accuracy of HIV infection classification, ultimately contributing to improved patient management and treatment strategies. These findings also highlight the scalability of the approach, showing that it can be efficiently adapted for large-scale use across various healthcare environments, including those with limited resources, making it suitable for widespread deployment in both high- and low-resource settings.

Background. Human immunodeficiency virus type 1 (HIV-1) subtypes differ in biological characteristics that may affect pathogenicity. Methods. We determined the HIV-1 subtype—specific rates of disease progression among 350 HIV-1 seroconverters. Subtype, viral load, and CD4+ cell count were determined. Cox proportional hazards regression modeling was used to estimate adjusted hazard ratios (HRs) of progression to acquired immunodeficiency syndrome (AIDS) (defined as a CD4+ cell count of ⩽250 cells/mm3) and to AIDS-associated death. Results. A total of 59.1% of study subjects had subtype D strains, 15.1% had subtype A, 21.1% had intersubtype recombinant subtypes, 4.3% had multiple subtypes, and 0.3% had subtype C. Of the 350 subjects, 129 (37%) progressed to AIDS, and 68 (19.5%) died of AIDS. The median time to AIDS onset was shorter for persons with subtype D(6.5 years), recombinant subtypes (5.6 years), or multiple subtypes (5.8 years), compared with persons with subtype A (8.0 years; P = .022). Relative to subtype A, adjusted HRs of progression to AIDS were 2.13 [95% confidence interval {CI}, 1.10–4.11] for subtype D, 2.16 [95% CI, 1.05–4.45] for recombinant subtypes, and 4.40 [95% CI, 1.71–11.3] for multiple subtypes. The risk of progression to death was significantly higher for subtype D(adjusted HR, 5.65; 95% CI, 1.37–23.4), recombinant subtypes (adjusted HR, 6.70; 95% CI, 1.56–28.8), and multiple subtypes (adjusted HR, 7.67; 95% CI, 1.27–46.3), compared with subtype A. Conclusions. HIV disease progression is affected by HIV-1 subtype. This finding may impact decisions on when to initiate antiretroviral therapy and may have implications for future trials of HIV-1 vaccines aimed at slowing disease progression.

Background Management of patients with chronic conditions relies on accurate measurement. It is unknown how transition to the ICD-10 coding system affected reporting of chronic condition rates over time. We measured chronic condition rates 2 years before and 1 year after the transition to ICD-10 to examine changes in prevalence rates and potential measurement issues in the Veterans Affairs (VA) health care system. Methods We developed definitions for 34 chronic conditions using ICD-9 and ICD-10 codes and compared the prevalence rates of these conditions from FY2014 to 2016 in a 20% random sample (1.0 million) of all VA patients. In each year we estimated the total number of patients diagnosed with the conditions. We regressed each condition on an indicator of ICD-10 (versus ICD-9) measurement to obtain the odds ratio associated with ICD-10. Results Condition prevalence estimates were similar for most conditions before and after ICD-10 transition. We found significant changes in a few exceptions. Alzheimer’s disease and spinal cord injury had more than twice the odds of being measured with ICD-10 compared to ICD-9. HIV/AIDS had one-third the odds, and arthritis had half the odds of being measured with ICD-10. Alcohol dependence and tobacco/nicotine dependence had half the odds of being measured in ICD-10. Conclusion Many chronic condition rates were consistent from FY14–16, and there did not appear to be widespread undercoding of conditions after ICD-10 transition. It is unknown whether increased sensitivity or undercoding led to decreases in mental health conditions.

WHO has proposed a public-health approach to antiretroviral therapy (ART) to enable scaling-up access to treatment for HIV-positive people in developing countries, recognising that the western model of specialist physician management and advanced laboratory monitoring is not feasible in resource-poor settings. In this approach, standardised simplified treatment protocols and decentralised service delivery enable treatment to be delivered to large numbers of HIV-positive adults and children through the public and private sector. Simplified tools and approaches to clinical decision-making, centred on the “four Ss”—when to: start drug treatment; substitute for toxicity; switch after treatment failure; and stop—enable lower level health-care workers to deliver care. Simple limited formularies have driven large-scale production of fixed-dose combinations for first-line treatment for adults and lowered prices, but to ensure access to ART in the poorest countries, the care and drugs should be given free at point of service delivery. Population-based surveillance for acquired and transmitted resistance is needed to address concerns that switching regimens on the basis of clinical criteria for failure alone could lead to widespread emergence of drug-resistant virus strains. The integrated management of adult or childhood illness (IMAI/IMCI) facilitates decentralised implementation that is integrated within existing health systems. Simplified operational guidelines, tools, and training materials enable clinical teams in primary-care and second-level facilities to deliver HIV prevention, HIV care, and ART, and to use a standardised patient-tracking system.

Viral suppression and viral breakthrough impact the humoral immune response to HIV infection. We evaluated the impact of viral suppression and viral breakthrough on results obtained with two cross-sectional HIV incidence assays. All samples were collected from adults in the US who were HIV infected for >2 years. Samples were tested with the BED capture enzyme immunoassay (BED-CEIA) which measures the proportion of IgG that is HIV-specific, and with an antibody avidity assay based on the Genetic Systems 1/2+ O ELISA. We tested 281 samples: (1) 30 samples from 18 patients with natural control of HIV-1 infection known as elite controllers or suppressors (2) 72 samples from 18 adults on antiretroviral therapy (ART), with 1 sample before and 2-6 samples after ART initiation, and (3) 179 samples from 20 virally-suppressed adults who had evidence of viral breakthrough receiving ART (>400 copies/ml HIV RNA) and with subsequent viral suppression. For elite suppressors, 10/18 had BED-CEIA values <0.8 normalized optical density units (OD-n) and these values did not change significantly over time. For patients receiving ART, 14/18 had BED-CEIA values that decreased over time, with a median decrease of 0.42 OD-n (range 0.10 to 0.63)/time point receiving ART. Three patterns of BED-CEIA values were observed during viral breakthrough: (1) values that increased then returned to pre-breakthrough values when viral suppression was re-established, (2) values that increased after viral breakthrough, and (3) values that did not change with viral breakthrough. Viral suppression and viral breakthrough were associated with changes in BED-CEIA values, reflecting changes in the proportion of HIV-specific IgG. These changes can result in misclassification of patients with long-term HIV infection as recently infected using the BED-CEIA, thereby influencing a falsely high value for cross-sectional incidence estimates.