Antiretroviral treatment (ART) initiation during the early stages of HIV-1 infection is associated with a higher probability of maintaining drug-free viral control during subsequent treatment interruptions, for reasons that remain unclear. Using samples from a randomized-controlled human clinical trial evaluating therapeutic HIV-1 vaccines, we here show that early ART commencement is frequently associated with accelerated and efficient selection of genome-intact HIV-1 proviruses in repressive chromatin locations during the first year after treatment initiation. This selection process was unaffected by vaccine-induced HIV-1-specific T cell responses. Single-cell proteogenomic profiling demonstrated that cells harboring intact HIV-1 displayed a discrete phenotypic signature of immune selection by innate immune responses, characterized by a slight but significant upregulation of HLA-C, HLA-G, the IL-10 receptor, and other markers involved in innate immune regulation. Together, these results suggest an accelerated immune selection of viral reservoir cells during early-treated HIV-1 infection that seems at least partially driven by innate immune responses.
Abstract Background Switching from boosted PIs to dolutegravir in people living with HIV (PLWH) with high cardiovascular risk improved plasma lipids at 48 weeks in the NEAT022 trial. Whether this strategy may have an impact on cardiovascular biomarkers is unknown. Methods We assessed 48 week changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury, and glomerular and tubular kidney injury. Results Of 415 PLWH randomized in the NEAT022 study, 313 (75.4%) remained on allocated therapy and had paired samples available. Soluble CD14 (–11%, P < 0.001) and adiponectin (–11%, P < 0.001) significantly declined and high-sensitive C-reactive protein (–13%, P = 0.069) and oxidized LDL (–13%, P = 0.084) tended to decrease with dolutegravir. Switching to dolutegravir remained significantly associated with soluble CD14 and adiponectin reductions after adjustment for baseline variables. There were inverse correlations between soluble CD14 and CD4 count changes (P = 0.05), and between adiponectin and BMI changes (P < 0.001). Conclusions Switching from boosted PIs to dolutegravir in PLWH with high cardiovascular risk led to soluble CD14 and adiponectin reductions at 48 weeks. While decreasing soluble CD14 may entail favourable health effects in PLWH, adiponectin reduction may reflect less insulin sensitivity associated with weight gain.
Objectives: Tenofovir DF (TDF) remains one of the preferred backbone agents for naive HIV patients starting antiretroviral treatment (ART). The impact of TDF on renal function and metabolic parameters may vary by anchor agent. We investigated the impact of TDF in combination with 3 different integrase inhibitors on tubular and glomerular function, and metabolic parameters in ART-naive patients.Methods: Sixty patients with normal renal function were randomised (20 per arm) to TDF/emtricitabine (FTC) plus either raltegravir (RAL) (400 mg b.d.), dolutegravir (DTG) or elvitegravir/cobicistat (EVG/c) for 48 weeks.Results: 57 patients completed the study. Significant increases in RBP/creatinine ratio at week 24 were seen in all arms [RAL +4.7 μg/mmol (CI 0.43 to 8.98, p = 0.032); DTG +4.96 μg/mmol (CI 0.77 to 9.15, p = 0.021); EVG/c +6.95 μg/mmol (CI 2.53 to 11.36, p = 0.002)], although this was not sustained to week 48 in the RAL arm. Similar changes across the arms were observed for urinary α1microglobulin (RAL +6.20 mg/L, p = 0.030; DTG +6.30 mg/L, p = 0.025; EVG/c +8.15 mg/L, p = 0.003). Urinary β2microglobulin significantly increased at week 24 with DTG and EVG/c but remained unchanged in the RAL arm. Glomerular filtration measured with CKD-EPI creatinine-cystatin C increased significantly in the RAL arm at week 24 through 48 but declined modestly in other two arms. Total and LDL cholesterol decreased in the RAL arm, but increased in the EVG/c arm, with no significant changes in the DTG arm. Weight increased significantly from baseline with DTG but not RAL or EVG/c.Conclusion: INSTIs in combination with TDF/FTC impact differently on tubular microproteinuria, eGFR, metabolic markers and weight. Use of TDF/FTC with RAL had the least tubular effects and the most favorable metabolic profile.
Abstract Background In the NEAT022 trial, switching from boosted PIs (PI/r) to dolutegravir in people with HIV (PWH) with high cardiovascular risk decreased plasma lipids, soluble CD14 and adiponectin, and showed consistent favourable, although non-significant, effects on carotid intima-media thickness (CIMT) progression at 48 weeks. We hereby communicate planned final 96 week results on biomarker changes and CIMT progression. Methods PWH on a PI/r-based triple therapy regimen were randomly assigned (1:1) to switch the PI/r component to dolutegravir either immediately (DTG-I group) or after 48 weeks (DTG-D group) and were followed up to 96 weeks. We assessed changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury and glomerular and tubular kidney injury, and right and left CIMT progression at 48 and 96 weeks. Results Of 415 PWH randomized, 287 (69%) and 143 (34%) contributed to the biomarker and CIMT substudies respectively. There were significant 96 week changes in biomarkers associated with inflammation, immune activation, oxidation, insulin resistance and myocardial injury. Most changes were favourable, except for adiponectin reduction, which may suggest higher insulin resistance. We were unable to detect significant changes in the progression of CIMT between arms or within arms at 96 weeks. Discussion After 96 weeks, switching from PI/r to dolutegravir in PWH with high cardiovascular risk led to significant changes in several biomarkers associated with cardiovascular disease. Although most changes were favourable, adiponectin reduction was not. There were non-significant changes in CIMT progression.
Abstract Introduction People living with HIV requiring admission to intensive care often receive enteral nutrition via feeding tubes. Enteral feeds contain cations which may interfere with dolutegravir (DTG) absorption due to chelation1. For this reason, temporal spacing (six hours before/ two hours after DTG administration2) is recommended, possibly leading to suboptimal caloric intake3. The clinical significance of the interaction between enteral feeds and DTG when co-administered is not fully understood and public data are sparse. Aim We aim to evaluate the impact and outcomes of co-administering DTG and enteral feeds. Methods Review of prospectively collected data on therapeutic drug monitoring (TDM) and electronic patient records of patients on DTG and enteral feeds, whilst in intensive care unit (ITU) between 2022 and 2023. Maximum (Cmax) and trough (Ctrough) DTG concentrations were measured and compared to reference ranges (DTG 50 mg once daily: Cmax 3340 ng/mL; Ctrough 830 ng/mL). All data were anonymised and collected as part of routine care for analysis. According to the National Research Ethics Service guidelines, further patient consent and ethical approval were not required. Results Six cases were identified with eight incidences of TDM sampling: 2 (33%) female; median age 34 (IQR 33-42); 3 (50%) non-white ethnicity; mean number of days on ITU 46 days; mean number of days into feeds 28 days; all (100%) suffered from hypoalbuminaemia (18-26 g/L). All patients were taking tenofovir-based regimens as their backbone antiretroviral therapy and once daily DTG, unless when co-administered with rifampicin where twice daily DTG is required to overcome enzyme induction effects of rifampicin. In three of the eight samples, temporal spacing with enteral feeds occurred as per SPC guidance2. The highest Cmax with once daily DTG seen in this cohort was 2201 ng/mL which was achieved without temporal spacing, whilst the lowest Ctrough (44 ng/mL) was observed in a different individual with sufficient temporal spacing. The viral loads measured while patients were receiving feeds varied, with 3 (50%) remaining suppressed. All (100%) patients had a fully suppressed viral load after enteral feeds ceased, including one patient who was naïve to treatment prior to admission with a high viral load. Discussion/Conclusion DTG Cmax were lower than those observed in literature regardless of temporal spacing from enteral feeds. Ctrough concentrations were also lower than expected in all cases. Six of eight Ctrough were lower than the DTG minimum effective concentration (MEC) of 300 ng/mL, however, only one was below IC90 for wildtype virus (64 ng/mL). Virological failure or onset of resistance was not observed in any of the patients. Multiple factors are likely to be contributing to low DTG concentrations, of which the most significant is likely impaired drug absorption, whilst nutritional feed co-administration seems to not be relevant. References 1. Song, I, Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. J Clin Pharmacol, 2015, 55(5), 490-496. 2. ViiV Healthcare UK Ltd, Summary of Product Characteristics (SmPC): Tivicay 50 mg Film-Coated Tablets, Last updated 04 Dec 2023. Available from: Tivicay 50 mg Film-Coated Tablets - Patient Information Leaflet (PIL) - (emc) (medicines.org.uk) [Accessed Apr 24]. 3. Peev, MP, Causes and consequences of interrupted enteral nutrition: a prospective observational study in critically ill surgical patients, JPEN J Parenter Enteral Nutr, 2015, 39(1), 21-27.
These guidelines are dedicated to the memory of Professor Stephen Lawn, a scientist and clinician whose pioneering work helped transform the management of TB in people living with HIV. The overall purpose of these guidelines is to help physicians manage adults with tuberculosis (TB)/human immunodeficiency virus (HIV) co-infection. Recommendations for the treatment of TB in HIV-positive adults are similar to those in HIV-negative adults. Of note, the term "HIV" refers to HIV-1 throughout these guidelines. The British HIV Association (BHIVA) fully revised and updated the Association's guideline development manual in 2011. Further updates have been carried out subsequently 1. Full details of the guideline development process, including conflict of interest policy, are outlined in the manual. BHIVA has adopted the modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for the assessment, evaluation and grading of evidence and development of recommendations (see below and Appendix 1) 2, 3. The scope, purpose and guideline topics were agreed by the writing group. Questions concerning each guideline topic were drafted and a systematic literature search was undertaken by an information scientist. Details of the search questions and strategy (including the definition of populations, interventions and outcomes) are outlined in Appendix 2. BHIVA guidelines for the treatment of TB/HIV co-infection were last published in 2011 4. For the 2017 guidelines, Medline, EMBASE and the Cochrane Library were searched between August 2015 and January 2016. Abstracts from selected conferences (see Appendix 2) were searched between August 2015 and January 2016. For each topic and healthcare question, evidence was identified and evaluated by writing group members with expertise in the field. Using the modified GRADE system, writing group members were responsible for assessing and grading the quality of evidence for predefined outcomes across studies and developing and grading the strength of recommendations. An important aspect of evaluating evidence is an understanding of the design and analysis of clinical trials, including the use of surrogate marker data. Decisions regarding the clinical importance of difference in outcomes were made by the writing group. Before final approval by the writing group, the guidelines were published online for public consultation and an external peer review was commissioned. BHIVA views the involvement of people living with HIV (PLWH) and community representatives in the guideline development process as essential. The writing group included two representatives appointed through the UK Community Advisory Board (UK-CAB) and community groups are specifically invited to participate in the public consultation process. The GRADE Working Group 2 has developed an approach to grading evidence that moves away from initial reliance on study design to consider the overall quality of evidence across outcomes. BHIVA has adopted the modified GRADE system for its guideline development (see Appendix 1). The advantages of the modified GRADE system are: (i) the grading system provides an informative, transparent summary for clinicians, PLWH and policymakers by combining an explicit evaluation of the strength of the recommendation with a judgement of the quality of the evidence for each recommendation, and (ii) the two-level grading system of recommendations has the merit of simplicity and provides clear direction to PLWH, clinicians and policymakers. The strength of recommendation is graded as 1 or 2 as follows: The strength of a recommendation is determined not only by the quality of evidence for defined outcomes but also by the balance between desirable and undesirable effects of a treatment or intervention, differences in values and preferences and, where appropriate, resource use. Each recommendation concerns a defined target population and is actionable. The quality of evidence is graded from A to D and for the purpose of these guidelines is defined as the following: In addition to graded recommendations, the BHIVA writing group has also included good practice points (GPPs), which are recommendations based on the clinical judgement and experience of the group. GPPs emphasise an area of important clinical practice for which there is not, nor is there likely to be, any significant research evidence. They address an aspect of treatment and care that is regarded as such sound clinical practice that healthcare professionals are unlikely to question it and where the alternative recommendation is deemed unacceptable. It must be emphasised that GPPs are not an alternative to evidence-based recommendations. The following measures have been or will be undertaken to disseminate and aid implementation of the guidelines: The guidelines will be fully updated and revised in 2021. However, the writing group will continue to meet regularly to consider new information from high-quality studies and publish amendments and addenda to the current recommendations before the full revision date where this is thought to be clinically important to ensure continued best clinical practice. These guidelines update the previously published BHIVA guidelines on the treatment of TB/HIV co-infection from 2011 1 and are designed to provide a clinical framework applicable to adults living with HIV in the UK who have TB. They do not include management of HIV-positive children with TB. The guidance is based on the evidence available, although some recommendations necessarily rely on expert opinion until further data become available. These guidelines should be used in conjunction with: The WHO reported in 2018 the following data for 2017 7: The incidence of TB in England is higher than in most Western European countries 8. Although it was declining during most of the 20th century, a steady increase was observed from the late 1980s to 2005. The annual incidence rates of TB among adults living with diagnosed HIV in England and Wales declined from 17.5 per 1000 (420/23,990) in 2008 to 4.4 per 1000 (300/68,350) in 2011 9. This trend is largely due to a decline in new HIV diagnoses among men and women born in countries of sub-Saharan Africa where the prevalence of both HIV and TB is high, as well as to an increase in total number of PLWH 10. TB incidence varies by demographic characteristics with rates among people born outside the UK of 7.7 per 1000 population (in 2011), women (6.7), those aged 25–39 years (10.5) and people of black African ethnicity (7.7). The risk of developing TB is estimated to be between 26 and 31 times greater in PLWH than among those without HIV infection. Thus, all individuals with TB, regardless of their perceived risk of HIV infection, should be offered an HIV test. In HIV co-infection, the clinical and radiographic presentation of TB may be atypical. Compared with the immune-competent population, TB/HIV-positive individuals with active pulmonary TB are more likely to have normal chest radiographs or sputum that is smear negative but culture positive 11, 5 (see Section 5 and Appendix 3). The clinician caring for HIV-positive individuals therefore needs to have a high index of suspicion for TB in symptomatic individuals, especially those who have lived in TB-endemic parts of the world. As the investigation and treatment of both TB and HIV infection is complex, it is mandatory to involve specialists in HIV, respiratory and/or infectious diseases. Treatment of TB benefits the individual and also the community. The aims of treatment are 1: Microscopic smear of clinical specimens remains an essential part of TB diagnosis. The quality of any investigation is related to the quality of the specimen and the clinical detail provided with the request. There must therefore be close liaison with the mycobacteriology laboratory. Results should be available within 1 working day. Use of molecular biology allows for early identification of mycobacteria and of genotypic (rifampicin/isoniazid) drug susceptibility. The Xpert MTB/RIF is an automated molecular test for identification of M. tuberculosis and of rpoB mutations conferring resistance to rifampicin. It is very specific (99%) and its sensitivity for smear-positive, culture-positive TB approaches 98%, compared with a sensitivity of 65% for microscopy 1. The sensitivity for rifampicin resistance is slightly lower (95%) than the sensitivity for M. tuberculosis identification (see Appendix 3). In smear-positive samples, its use can allow rapid confirmation that AFB are not M. tuberculosis, potentially avoiding unnecessary treatment and infection-control measures 2. The newer Xpert MTB/RIF Ultra (Cepheid) has been shown to have improved sensitivity but lower specificity in HIV-positive individuals compared with Xpert MTB/RIF 3 and is recommended by WHO for sputum and selected extrapulmonary samples 4. Despite the high sensitivity and specificity, molecular biology tests have to be performed together with cultures and phenotypic drug susceptibility testing. All specimens, even those negative for M. tuberculosis on polymerase chain reaction (PCR), still require culture because a negative PCR does not exclude M. tuberculosis and a positive PCR does not currently indicate the full drug-susceptibility profile 5, 6. Whole-genome sequencing (WGS) is available in the UK and is currently being used to identify clusters and to detect genotypic resistance but it requires a culture isolate; Xpert MTB/RIF can be performed on a primary sample (without the need for a positive culture), for example a sputum sample, and detects M. tuberculosis and mutations associated with rifampicin resistance more quickly. The sensitivity and specificity of IGRAs in HIV-positive people is suboptimal when used alone to "rule in" or "rule out" active TB disease 7-10. IGRAs should not be used to diagnose or exclude active TB (see Appendix 3). Identification of mycobacteria is performed at reference centres, and is based on molecular techniques, morphology, growth and biochemical characteristics. Liquid culture medium provides more rapid results than solid medium and M. tuberculosis can usually be grown in 7–28 days. Drug-susceptibility tests using WGS and phenotypic assays are usually available within 10–21 days from receipt of isolates by the laboratory. The commonest presentation of TB in the CNS is tuberculous meningitis (TBM), which is the most severe form of TB with the highest mortality (between 20% and 50%) and morbidity, as diagnosis and treatment are often delayed 11. Less commonly it can manifest as tuberculous encephalitis, intracranial tuberculomas or tuberculous brain abscess(es) 11. Early diagnosis is challenging due to the non-specific symptoms of TBM, such as fever, headache and vomiting, with gradual onset and duration, often lasting for weeks. Meningism, with or without focal neurological deficits, behavioural changes and alterations in consciousness are also features of TBM. The main investigations are cranial imaging (magnetic resonance imaging) and lumbar puncture for CSF analysis. Significant CSF findings in TBM include a mainly mononucleate cell (lymphocytic predominant) pleocytosis in 60–85% of patients, in which the total white count ranges between 100 and 500 cells/mm3. In advanced HIV, CSF can be acellular. Low CSF glucose levels (usually less than 2.5 mmol/L) and high protein levels, typically between 1 and 5 g/L, are also suggestive of TBM. Identification of M. tuberculosis in CSF by culture remains the "gold standard", but has a limited sensitivity (ranging between 10% and 60%). Microscopy with Ziehl–Neelsen staining for AFB detection has a low sensitivity in the CSF (10–60%), due to the small number of tubercle bacilli usually present. Large volumes (minimum 6 mL) of CSF should be examined to enhance the sensitivity 12, 13. The WHO recommendation is to use Xpert MTB/RIF as the preferred initial test for diagnosis of TB meningitis instead of conventional tests (see Appendix 3). However, a negative Xpert MTB/RIF result on a CSF sample does not exclude TB meningitis. Where available, use of Xpert MTB/RIF Ultra is preferred as it has a higher sensitivity than Xpert MTB/RIF in diagnosing TB meningitis 14. Adenosine deaminase (ADA) (a predominant T lymphocyte enzyme, which catalyses the conversion of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively) measurement can also be of use in the diagnosis of TB meningitis. Levels in CSF are significantly elevated in TBM with a sensitivity and specificity ranging from 60–90% and 80–90%, respectively 12. However, the ADA assay has not been standardised and the "cut-off" level that defines a positive result has not been determined, and consequently it is not recommended as part of routine investigation for TB meningitis 15, 16. Where HIV is endemic, TB pleuritis is the most common cause of a lymphocytic effusion, thought to result from primary infection in 30% of patients 18. In individuals with a suspected TB pleural effusion it is important to obtain cultures on pulmonary (generally sputum or bronchoscopic) samples, including in the absence of obvious parenchymal involvement as, even in individuals with normal underlying lung parenchyma on chest radiography, the yield of sputum culture in induced samples approaches 55% 17. The diagnosis of TB pleuritis is also made by detection of M. tuberculosis in pleural fluid or pleural biopsy specimens, or by assumption if M. tuberculosis is identified in sputum and there is co-existent pleural effusion, either by microscopy and/or culture or by the histological demonstration in the pleura of caseating granulomas together with AFB. Microscopy for AFB in the pleural fluid can identify M. tuberculosis in approximately 20% of HIV-positive individuals with pleural TB, though the yield can be up to 50% 19 if the patient's CD4+ cell count is less than 100 cells/mm3 19, 20. TB PCR has a low sensitivity for diagnosis of pleural TB. A pooled analysis of data from 20 studies that assessed the use of pleural fluid molecular diagnostic tests showed a high specificity (97% for commercial and 91% for in-house tests) but a generally poor and variable sensitivity (62% for commercial and 76.5% for in-house tests) 6. Where available, medical thoracoscopy may be useful in the diagnosis of pleural TB. In settings of low TB incidence, thoracoscopy has proved to be an effective diagnostic tool in HIV-negative patients, with a pooled sensitivity for TB on culture and histology of 93%, in combination with ADA, and a specificity of 100% 18. Measurement and quantification of ADA in pleural fluid may also be useful. Individuals who present with a lymphocytic predominant exudative pleural effusion and raised ADA level have a high probability of having pleural TB (see Appendix 3). Data on the accuracy of molecular biological tests for diagnosis of TB in non-respiratory specimens have been reported in two systematic reviews (SRs), which both support their use in diagnosis of extrapulmonary TB 21, 22 (see Appendix 3). The urine lateral flow lipoarabinomannan (LF-LAM) assay is a point-of-care test for active TB (see Appendix 3). Its sensitivity is highest in individuals with a CD4+ cell count <100 cells/mm3 23. Therefore it represents a useful adjunctive diagnostic for individuals with CD4+cell counts <100 cells/mm3 and in those who present with serious illness of unknown cause. Mycobacterial blood culture has also proven useful in diagnosis of disseminated TB in patients with low CD4+ cell counts (sensitivity 20–40%) 24. The cytopathological diagnosis of TB is based on finding AFB on Ziehl–Neelsen staining of tissue or a cytological preparation (e.g. a lymph node aspirate). Supplementary supportive evidence is provided by the finding of macrophage granulomas with or without necrosis. The finding of AFB in a cytopathological specimen should be critically interpreted in the context of a patient's presentation, their imaging findings and results from other laboratory investigations. It is important to precisely identify AFB where possible, using culture and molecular diagnostic techniques. The classical lesions of TB include epithelioid cell granulomas with or without Langhans giant cells and caseation necrosis, and AFB. Other diseases, infectious and non-infectious, have similar granuloma morphology as TB, and fungal staining must always be undertaken to exclude mycosis (e.g. histoplasmosis) as the relevant agent. If TB is diagnosed histopathologically, but standard treatment appears ineffective, non-tuberculous mycobacterial infection should be considered. Other differential diagnoses that can mimic TB include: sarcoidosis, histoplasmosis, nocardiosis, leishmaniasis, granulomatous reaction to local tumour, common variable immunodeficiency syndromes, vasculitis syndromes, autoimmune diseases and Gram-negative infections (e.g. brucellosis and melioidosis). In difficult cases, multidisciplinary consultation is invaluable, where all the information – clinical, radiological, pathological, molecular diagnostics and results of treatment – can be critically reviewed. Because the presence of granulomas is regarded as typical of TB, differential diagnoses should be considered, especially if response to treatment is not progressing as expected. MDR-TB definition: resistance to at least isoniazid and rifampicin. Pre-extensively drug-resistant (XDR)-TB definition: resistance to isoniazid and rifampicin and either a fluoroquinolone or second-line injectable agent but not both. XDR-TB definition: resistance to isoniazid and rifampicin and quinolones and at least one second-line injectable (e.g. amikacin). The number and proportion (1.7%) of TB cases with initial rifampicin-resistant/MDR-TB in England has been relatively stable since the peak in 2011 (89, 1.8%). Public Health England reported that in England in 2017, 3.3% (3/90) of patients with both HIV and culture-positive TB had rifampicin-resistant/MDR-TB while 7.8% (7/90) had isoniazid resistance without MDR-TB 25. The presence of the following risk factors should always raise suspicion of possible drug-resistant TB: Molecular tests for rifampicin resistance are useful when MDR-TB is suspected (e.g. in a recent immigrant from an area with a high prevalence of rifampicin-resistant disease), as a large proportion of rifampicin-resistant strains have isoniazid resistance as well 26 (see Appendix 3). In the UK, the majority of cases of TB occur in individuals from high- and medium-incidence settings 1, suggesting a substantial role for reactivation of latent infection. Individuals with LTBI are at increased risk of developing active TB, especially if they have recently acquired M. tuberculosis or are immunocompromised 1. HIV-positive individuals from countries with a high TB incidence, especially from sub-Saharan Africa, often present with TB as the first manifestation of immunosuppression, and mortality among HIV-positive persons with TB remains high 2. We define high and medium TB incidence as ≥151/100,000 and 40–150/100,000 person-years, respectively 3 (see 4, 5 for up-to-date TB incidence by country). LTBI testing for new entrants to the UK from countries with high TB incidence is an effective as well as cost-effective public health intervention 6 and is recommended by NICE 3. WHO guidelines for countries with a low TB burden 7 advise testing for LTBI in all HIV-positive individuals. However, it has recently been shown that this approach is unlikely to be cost-effective in the UK 8. The risk of progression to active TB in the general population is highest within the first 2–3 years following M. tuberculosis infection and HIV-positive individuals with LTBI are much more likely to progress to active TB than HIV-negative individuals 9. Increased incidence of active TB is associated with low CD4+ cell counts, including while on ART, and with shorter time on ART 10-13. Long-term successful ART substantially reduces the risk of TB among HIV-positive individuals, although it should be noted that in populations from countries of high TB incidence, such as those of sub-Saharan Africa, the background risk of TB (irrespective of HIV co-infection) is already high 2 (see Table 6.1). For clinical purposes, a positive IGRA result in an individual with no clinical or radiological evidence of active TB indicates LTBI. Before testing for or treating LTBI, active TB should be excluded with a detailed history and examination. The advantages of IGRAs include the practical benefit of a single blood test with no need for patient recall to read the result. These assays are more costly than TST, although the savings may be offset by, for instance, healthcare worker time and possible better specificity leading to fewer individuals being treated for LTBI 6, 14. Although the proportion of individuals with a positive IGRA result after treatment for active TB decreases with time 15, a positive result even several years after treatment could still indicate previously treated disease. In that population, treatment for LTBI may be considered only if there has been significant new exposure. NICE recommends testing for LTBI with an IGRA and concurrent TST in HIV-positive individuals 3. However, in view of operational and cost disadvantages of TST, a reduced sensitivity among those with low CD4+ cell counts, and false-positive results due to prior Bacillus Calmette–Guérin (BCG) vaccination and exposure to non-tuberculous mycobacteria, plus limited data comparing strategies of using IGRA and TST to identify LTBI among those with low CD4+ cell counts, we recommend the sole use of IGRA in a UK setting (see Appendix 4). The ongoing PREDICT study 16 may inform a more evidence-based future recommendation. Some individuals born in low-incidence countries, including the UK, will be at greater risk of developing TB than others. We recommend considering testing for and treating LTBI in those from low-incidence countries (e.g. the UK) who have additional risk factors such as exposure to a known TB case (which should be identified through routine contact tracing) or travel to or periods of time (we suggest >12 months) spent consecutively in higher-incidence countries 3. Particular additional factors of relevance to HIV-positive individuals include: a history of working in medical settings in TB endemic areas; injecting drug use; stage 4/5 chronic kidney disease; diabetes mellitus; receipt of chemotherapy for malignancy; immunosuppression following organ transplantation; and biological disease modifiers for inflammatory conditions. In contrast to the previous guidelines, we now suggest that services make local arrangements for managing the increase in numbers requiring testing (and treating) for LTBI, depending on numbers of patients and service capacity. We suggest that it is acceptable to discuss and offer testing to those at risk at their routine follow-up appointments. In pregnant women newly diagnosed with HIV, we recommend testing and treating LTBI in the same way as in non-pregnant individuals, including use of chest radiography if clinically indicated. In making this recommendation, we have considered the risk of toxicity from treatment for LTBI. Hepatotoxicity in particular is associated with other co-existing risk factors (see below). We suggest using an algorithm (Fig. 6.1) similar to that proposed by the WHO to exclude active TB 17. Other investigations may be necessary, for example chest radiography or lymph node biopsy (if lymphadenopathy is detected clinically or through imaging). It is important to consider the possibility of subclinical TB prior to starting ART because of the risk of IRIS, particularly among those with low CD4+ cell counts 18 (see Section 12 and Appendix 5). There have been many short-term controlled trials in HIV-positive individuals showing a protective effect of treatment for LTBI with an efficacy ranging from 60% to 90% (see Appendix 4). Another regimen that might be considered, depending on individual circumstances and concomitant medications, and for which there is evidence of equivalent efficacy is: Regimens 2 and 3 have been shown to be equivalent to regimen 1 in terms of TB-free survival 19 and in the prevention of incident TB after treatment and hepatotoxicity of grade 3 or above 20, 21. A regimen of rifampicin plus pyrazinamide has been shown to be effective in preventing active TB, but there is evidence that pyrazinamide-containing regimens cause more hepatotoxicity than isoniazid alone and they are therefore not recommended 21-23. Care must be taken to avoid DDIs with ART. Rifapentine-based regimens for LTBI treatment are not discussed in this guideline, given the lack of availability of rifapentine in the UK. Mild, non-specific hepatotoxicity occurs in up to 20% of individuals taking isoniazid, but most of this is subclinical and evidenced only by mildly elevated levels of serum aminotransferases (usually <100 IU/L) 24. During isoniazid therapy for LTBI, clinical symptomatic hepatotoxicity is rare (<1%) but can be fatal, particularly if associated with other factors, such as excessive alcohol consumption, older age (e.g. >65 years), slow acetylator status or concurrent liver disease 25, 26. Most hepatotoxicity is self-limiting and isoniazid can be continued with clinical and laboratory monitoring. The risk of severe (AIDS Clinical Trials Group [ACTG] grade 3 or above) hepatotoxicity associated with isoniazid therapy for LTBI is 0.1–0.3% according to different studies 27, 28. Rifampicin-containing regimens should also be prescribed with caution due to potential DDIs. When considering treatment for LTBI, the potential benefit needs to be carefully balanced against the risk of drug-related adverse events. Individuals treated for LTBI should be informed of symptoms of hepatotoxicity, such as anorexia, nausea, vomiting, abdominal discomfort, persistent fatigue or weakness, dark-coloured urine, pale stools or jaundice. Patients experiencing these symptoms, particularly those aged >65 years, should be advised to contact their healthcare providers, and if there is a delay in doing so should stop treatment immediately. Studies of isoniazid treatment for LTBI have included the risk of isoniazid-resistant active TB as a secondary outcome. Although there are theoretical concerns that widespread isoniazid monotherapy might accelerate the emergence of drug-resistant TB 29, evidence from trials has shown no significant association between anti-TB drug resistance and prior use of isoniazid and/or rifamycins for LTBI 19, 25, 30. Studies in areas of high TB incidence have shown that isoniazid prophylaxis post-treatment achieves short-term reductions in rates of TB 31, 32 and that long-term isoniazid therapy (36 months in trials) reduces TB incidence 33, 34 among HIV-positive individuals. Such a strategy may in fact prevent reinfection, which is more common than true reactivation in such settings 35. For maximum benefit the isoniazid would need to be continued long term, or at least until the CD4+ cell count had substantially risen on ART, and there are no data to support such an approach, particularly in settings of lower TB incidence. It is clear that ART protects against TB. It should be initiated if not already in place, and continued, for those with active and LTBI (see Section 9 and Appendix 6). Continuation of TB prophylaxis after treatment of active TB is therefore not recommended in the UK setting, but ART should be continued. For HIV-positive individuals with a history of exposure to drug-resistant TB (resistant to one or more first-line drugs), there are limited data to support any particular course of action. To help management of such cases an individualised management plan might be formulated from collaboration between the individual, the HIV physician, a specialist in the management of drug-resistant TB, and public health services. Options include: inform and advise the patient regarding early presentation with any symptoms of possible TB; use a treatment regimen for LTBI to which the source patient's isolate is considered to be susceptible; and use a standard LTBI regimen if there is thought to have been pre-existing LTBI before the contact with drug-resistant disease occurred. The treatment of drug-susceptible TB evolved through an international clinical trial programme to the current standard of care: short-course chemotherapy, consisting of 2 months of rifampicin, isoniazid, pyrazinamide and ethambutol (intensive phase), followed by 4 months of rifampicin and isoniazid (continuation phase) (2RHZE/4RH) 1, 2 (see Table 7.1). We recommend the use of daily fixed-dose combinations, where available. Several recent attempts to shorten TB therapy to 4 months (e.g. by using fluoroquinolones) have proved unsuccessful, with high relapse rates 3-6. Intermittent administration of TB therapy should be avoided during the induction phase in HIV-positive individuals, as this strategy has been associated with acquired rifamycin resistance 7. There is no evidence that individuals with disseminated TB should receive more prolonged therapy unless there is CNS involvement. Many clinicians use extended treatment regimens (up to 12 months, as per NICE guidance 8) for CNS TB (i.e. TB meningitis) even though 6–9 months may be sufficient. Rifabutin is a rifamycin with similar activity to rifampicin against M. tuberculosis 9-11 although no trials have been conducted in individuals receiving ART. The main advantage of rifabutin is that it allows the co-administration of (ritonavir-boosted) PIs (see Section 10 and Appendix 7). Corticosteroids should be used as an adjunct to TB therapy to reduce the immune/inflammatory response to M. tuberculosis in those with meningitis. An RCT of individuals with TB meningitis showed a 31% reduction in mortality among those who received adjunctive dexamethasone during t
Persistence of HIV through integration into host DNA in CD4+ T cells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8+ T cells are triggered to kill infected CD4+ T cells through recognition of histocompatibility leukocyte antigen (HLA) class I-bound peptides derived from incoming virions. However, this has been reported only in individuals with "beneficial" HLA alleles that are associated with superior HIV control. Through interrogation of the pre-integration immunopeptidome, we obtain proof of early presentation of a virion-derived HLA-A∗02:01-restricted epitope, FLGKIWPSH (FH9), located in Gag Spacer Peptide 2 (SP2). FH9-specific CD8+ T cell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4+ T cells prior to virus production in vitro. Our data show that non-beneficial HLA class I alleles can elicit an effective antiviral response through early presentation of HIV virion-derived epitopes and also demonstrate the importance of SP2 as an immune target.
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