Anna Maria Geretti

British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008

This summary document is an update to the full British HIV Association (BHIVA) Treatment Guidelines published in HIV Medicine in July 2005 (Volume 6, Supplement 2). Only the ‘What to start with’ and ‘Treatment-experienced patients’ sections have been completely rewritten. The tables of recommendations (Tables 1–7) have also been updated to include new data. Please refer to the full guidelines for more information.

Low-Frequency HIV-1 Drug Resistance Mutations and Risk of NNRTI-Based Antiretroviral Treatment Failure A Systematic Review and Pooled Analysis

CONTEXT Presence of low-frequency, or minority, human immunodeficiency virus type 1 (HIV-1) drug resistance mutations may adversely affect response to antiretroviral treatment (ART), but evidence regarding the effects of such mutations on the effectiveness of first-line ART is conflicting. OBJECTIVE To evaluate the association of preexisting drug-resistant HIV-1 minority variants with risk of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral virologic failure. DATA SOURCES Systematic review of published and unpublished studies in PubMed (1966 through December 2010), EMBASE (1974 through December 2010), conference abstracts, and article references. Authors of all studies were contacted for detailed laboratory, ART, and adherence data. STUDY SELECTION AND DATA ABSTRACTION Studies involving ART-naive participants initiating NNRTI-based regimens were included. Participants were included if all drugs in their ART regimen were fully active by standard HIV drug resistance testing. Cox proportional hazard models using pooled patient-level data were used to estimate the risk of virologic failure based on a Prentice weighted case-cohort analysis stratified by study. DATA SYNTHESIS Individual data from 10 studies and 985 participants were available for the primary analysis. Low-frequency drug resistance mutations were detected in 187 participants, including 117 of 808 patients in the cohort studies. Low-frequency HIV-1 drug resistance mutations were associated with an increased risk of virologic failure (hazard ratio (HR], 2.3 [95% confidence interval {CI}, 1.7-3.3]; P < .001) after controlling for medication adherence, race/ethnicity, baseline CD4 cell count, and plasma HIV-1 RNA levels. Increased risk of virologic failure was most strongly associated with minority variants resistant to NNRTIs (HR, 2.6 [95% CI, 1.9-3.5]; P < .001). Among participants from the cohort studies, 35% of those with detectable minority variants experienced virologic failure compared with 15% of those without minority variants. The presence of minority variants was associated with 2.5 to 3 times the risk of virologic failure at either 95% or greater or less than 95% overall medication adherence. A dose-dependent increased risk of virologic failure was found in participants with a higher proportion or quantity of drug-resistant variants. CONCLUSION In a pooled analysis, low-frequency HIV-1 drug resistance mutations, particularly involving NNRTI resistance, were significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.

European guidelines on the clinical management of HIV-1 tropism testing

Viral tropism is the ability of viruses to enter and infect specific host cells and is based on the ability of viruses to bind to receptors on those cells. Testing for HIV tropism is recommended before prescribing a chemokine receptor blocker. In most European countries, HIV tropism is identified with tropism phenotype testing. New data support genotype analysis of the HIV third hypervariable loop (V3) for the identification of tropism. The European Consensus Group on clinical management of tropism testing was established to make recommendations to clinicians and clinical virologists. The panel recommends HIV-tropism testing for the following groups: drug-naive patients in whom toxic effects are anticipated or for whom few treatment options are available; patients who have poor tolerability to or toxic effects from current treatment or who have CNS pathology; and patients for whom therapy has failed and a change in treatment is considered. In general, an enhanced sensitivity Trofile assay and V3 population genotyping are the recommended methods. Genotypic methods are anticipated to be used more frequently in the clinical setting because of their greater accessibility, lower cost, and faster turnaround time than other methods. For the interpretation of V3 loop genotyping, clinically validated systems should be used when possible. Laboratories doing HIV tropism tests should have adequate quality assurance measures. Similarly, close collaboration between HIV clinicians and virologists is needed to ensure adequate diagnostic and treatment decisions.

Human immunodeficiency virus type 1 Rev- and Tat-specific cytotoxic T lymphocyte frequencies inversely correlate with rapid progression to AIDS

Immunological correlates of AIDS-free survival after human immunodeficiency virus type 1 (HIV-1) infection are largely unknown. Cytotoxic T lymphocyte (CTL) responses are generally believed to be a major component of protective immunity against viral infections. However, the relationship between HIV-1-specific CTL responses and disease progression rate is presently unclear. Here we show in twelve HIV-1-infected individuals that detection of Rev-specific CTL precursors (CTLp) early in the asymptomatic stage, as well as detection of Rev- and Tat-specific CTLp later during follow-up, inversely correlate with rapid disease progression. No such correlation was found for detection of CTLp against Gag, RT or Nef. Further studies are required to determine whether a protective mechanism is indeed the basis of the observed correlation. The data presented are in agreement with the hypothesis that CTL against proteins that are important for early viral transcription and translation are of particular importance in protection from rapid disease progression.

HIV-1 subtypes: epidemiology and significance for HIV management.

Purpose of review This review presents an update on the molecular epidemic patterns of HIV-1 infection and the effects of subtype-related genetic variability on transmission, disease progression, response to antiretroviral therapy and drug-resistance pathways. Recent findings The molecular epidemiology of HIV-1 infection is complex and evolving. The emergence of new variants reflects HIV-1 prevalence, subtype epidemiology and risk-behaviour patterns in different geographical areas. Evidence indicates that certain subtypes may have a transmission advantage while others display higher replicative efficiency. The molecular mechanisms underlying these differences are being identified and include both virus- and host-related factors. Although drug susceptibility varies and clinical evidence remains limited, current antiretroviral regimens appear to have comparable efficacy in patients infected with B and non-B subtypes. Subtype-related variability influences resistance pathways. However, the major treatment-associated resistance mutations seen in subtype B also confer resistance in non-B subtypes and vice versa. Summary Genetic differences among HIV-1 variants can influence the virus biological properties, susceptibility to existing and candidate antiretroviral drugs, and evolution of antiretroviral drug resistance. Further studies are required to define the impact of this variability on risk of transmission, disease outcomes, responses to antiretroviral therapy and resistance pathways. Meanwhile, plasma viral load and CD4 count remain the important predictors of disease outcome, regardless of the infecting subtype. Current antiretroviral regimens can be used reliably to treat patients with both B and non-B subtypes, and resistance interpretation algorithms provide adequate guidance. The limitations of current evidence should be acknowledged and instigate ongoing vigilance.

Role of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 on apoptosis‐Prone CD8 T cells in persistent hepatitis B virus infection

An excess of coinhibitory signals has been proposed to drive the T‐cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 (CTLA‐4) to CD8 T cell tolerance in chronic hepatitis B virus (HBV) infection (CHB). CD8 T cells in patients with CHB have an increased propensity to express the coinhibitory receptor CTLA‐4 and this correlates with viral load. CTLA‐4 is up‐regulated on those HBV‐specific CD8 T cells with the highest levels of the proapoptotic protein Bim, which we have previously shown mediates their premature attrition; abrogation of CTLA‐4‐mediated coinhibition can reduce Bim expression. Longitudinal study of CHB patients beginning antiviral therapy reveals that HBV DNA suppression induces transient reconstitution of HBV‐specific CD8 T cells but does not reprogram their CTLA‐4hiBimhi tolerogenic phenotype. Blocking CTLA‐4 is able to increase the expansion of interferon gamma (IFN‐γ)‐producing HBV‐specific CD8 T cells in both the peripheral and intrahepatic compartments. The rescue of anti‐HBV responses by either CTLA‐4 or PD‐L1 blockade is nonredundant. Conclusion: CTLA‐4 is expressed by HBV‐specific CD8 T cells with high levels of Bim and helps to drive this proapoptotic phenotype. CTLA‐4 blockade could form one arm of a therapeutic approach to modulate the diverse patterns of coregulation of T‐cell exhaustion in this heterogeneous disease. (HEPATOLOGY 2011;)

British HIV Association guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals 2011.

1. Levels of evidence 1.1 Reference 2. Introduction 3. Auditable targets 4. Table summaries 4.1 Initial diagnosis 4.2 Assessment of ART‐naïve individuals 4.3 ART initiation 4.4 Initial assessment following commencement of ART 4.5 Routine monitoring on ART 4.6 References 5. Newly diagnosed and transferring HIV‐positive individuals 5.1 Initial HIV‐1 diagnosis 5.2 Tests to determine whether acquisition of HIV infection is recent 5.3 Individuals transferring care from a different HIV healthcare setting 5.4 Communication with general practitioners and shared care 5.5 Recommendations 5.6 References 6. Patient history 6.1 Initial HIV‐1 diagnosis 6.2 Monitoring of ART‐naïve patients 6.3 Pre‐ART initiation assessment 6.4 Monitoring individuals established on ART 6.5 Assessment of adherence 6.6 Recommendations 6.7 References 7. Examination 7.1 Recommendations 8. Identifying the need for psychological support 8.1 References 9. Assessment of immune status 9.1 CD4 T cell counts 9.2 CD4 T cell percentage 9.3 References 10. HIV viral load 10.1 Initial diagnosis/ART naïve 10.2 Post ART initiation 10.3 Individuals established on ART 10.4 Recommendations 10.5 References 11. Technical aspects of viral load testing 11.1 References 12. Viral load kinetics during ART and viral load ‘blips’ 12.1 References 13. Proviral DNA load 13.1 References 14. Resistance testing 14.1 Initial HIV‐1 diagnosis 14.2 ART‐naïve 14.3 Post treatment initiation 14.4 ART‐experienced 14.5 References 15. Subtype determination 15.1 Disease progression 15.2 Transmission 15.3 Performance of molecular diagnostic assays 15.4 Response to therapy 15.5 Development of drug resistance 15.6 References 16. Other tests to guide use of specific antiretroviral agents 16.1 Tropism testing 16.2 HLA B*5701 testing 16.3 References 17. Therapeutic drug monitoring 17.1 Recommendations 17.2 References 18. Biochemistry testing 18.1 Introduction 18.2 Liver function 18.3 Renal function 18.4 Dyslipidaemia in HIV‐infected individuals 18.5 Other biomarkers 18.6 Bone disease in HIV‐infected patients 18.7 References 19. Haematology 19.1 Haematological assessment and monitoring 19.2 Recommendations 19.3 References 20. Serology 20.1 Overview 20.2 Hepatitis viruses 20.3 Herpes viruses 20.4 Measles and rubella 20.5 Cytomegalovirus (CMV) 20.6 References 21. Other microbiological screening 21.1 Tuberculosis screening 21.2 Toxoplasma serology 21.3 Tropical screening 21.4 References 22. Sexual health screening including anal and cervical cytology 22.1 Sexual history taking, counselling and sexually transmitted infection (STI) screening 22.2 Cervical and anal cytology 22.3 Recommendations 22.4 References 23. Routine monitoring recommended for specific patient groups 23.1 Women 23.2 Older age 23.3 Injecting drug users 23.4 Individuals coinfected with HBV and HCV 23.5 Late presenters 23.6 References Appendix

Effect of HIV-1 subtype on virologic and immunologic response to starting highly active antiretroviral therapy.

BACKGROUND It has been proposed that subtype-related human immunodeficiency virus type 1 (HIV-1) variability may influence virologic and immunologic responses to highly active antiretroviral therapy (HAART). Studies to date, however, have described treatment outcomes predominantly in persons with subtype B infection or compared subtype B with diverse non-B subtypes grouped together. METHODS With use of data from the linked UK Collaborative Group on HIV Drug Resistance and the UK Collaborative HIV Cohort Study databases, time to viral load undetectability (viral load, <50 copies/mL), time to virologic rebound (viral load, >1000 copies/mL), and increases in the CD4 cell count were compared for a median of 39 months (interquartile range, 23-67 months) in drug-naive patients infected with subtype B (n=1550), subtype C (n=272), subtype A (n=66), circulating recombinant form AG (n=57), or subtype D (n=41) disease who started HAART. RESULTS Overall, 1906 (90%) of 2116 patients achieved viral load undetectability within 12 months after they started HAART, of whom 335 (18%) subsequently experienced virologic rebound. In adjusted analyses, viral load suppression occurred more rapidly in patients infected with subtype C (hazard ratio, 1.16; 95% confidence interval, 1.01-1.33; P=.04) and subtype A (hazard ratio, 1.35; 95% confidence interval, 1.04-1.74; P=.02) relative to subtype B infection. The virologic rebound occurred marginally more rapidly in patients with subtype C infection (hazard ratio, 1.40; 95% confidence interval, 1.00-1.95; P=.05), but the hazard of virologic rebound was similar with other subtypes. Although persons with subtype B infection showed higher baseline CD4 cell counts and maintained the advantage throughout therapy, CD4 cell count recovery occurred at similar rates with all subtypes. CONCLUSIONS Patients infected with prevalent non-B subtypes were as likely to achieve viral load suppression as persons infected with subtype B and showed comparable rates of CD4 cell count recovery. HAART achieves excellent outcomes regardless of the infecting subtype.

Plasma HIV-1 RNA Detection Below 50 Copies/mL and Risk of Virologic Rebound in Patients Receiving Highly Active Antiretroviral Therapy

BACKGROUND Plasma human immunodeficiency virus type 1 (HIV-1) RNA suppression <50 copies/mL is regarded as the optimal outcome of highly active antiretroviral therapy (HAART). Current viral load (VL) assays show increased sensitivity, but the significance of RNA detection <50 copies/mL is unclear. METHODS This study investigated the virologic outcomes of 1247 patients with VL <50 copies/mL at an arbitrary time point during HAART (= T0), according to whether the actual, unreported (T0)VL was 40-49 copies/mL, RNA detected <40 copies/mL (RNA(+)), or RNA not detected (RNA(-)), as measured by the Abbott Real Time assay. Predictors of rebound >50 and >400 copies/mL over 12 months following T0 were analyzed with Cox proportional hazards models incorporating the (T0)VL and demographic and clinical data. RESULTS Rebound rates >50 copies/mL were 34.2% for (T0)VL 40-49 copies/mL, 11.3% for RNA(+), and 4.0% for RNA(-); rebound rates >400 copies/mL were 13.0%, 3.8%, and 1.2%, respectively. The adjusted hazard ratios for rebound >50 copies/mL were 4.67 (95% confidence interval, 2.91-7.47; P < .0001) and 1.97 (1.25-3.11; P < .0001) with (T0)VL 40-49 copies/mL and RNA(+), respectively, relative to RNA(-), and 6.91 (2.90-16.47; P < .0001) and 2.88 (1.24-6.69; P < .0001), respectively, for rebound >400 copies/mL. The association was independent of adherence levels. CONCLUSIONS In treated patients monitored by RealTime, a VL of 40-49 copies/mL and, to a lesser extent, RNA detection <40 copies/mL predict rebound >50 and >400 copies/mL independently of other recognized determinants. The goal of HAART may need to be revised to a lower cutoff than 50 copies/mL.

British HIV Association guidelines for immunization of HIV-infected adults 2008.

Table of contents 1.0 Introduction 1.1 General principles of immunization in HIVinfected adults 1.2 Practical aspects of immunization and general contraindication 2.0 Anthrax 2.1 Background 2.2 Epidemiology and risk groups 2.3 Anthrax vaccine 2.3.1 Vaccine efficacy 2.3.2 Vaccine safety 2.4 Recommendations for anthrax pre-exposure prophylaxis in HIV-infected adults 2.5 Post-exposure prophylaxis 3.0 Cholera 3.1 Background 3.2 Epidemiology and risk groups 3.3 Cholera vaccine 3.3.1 Vaccine efficacy 3.3.2 Vaccine safety 3.3.3 Contraindications 3.4 Recommendations for cholera pre-exposure prophylaxis in HIV-infected adults 4.0 Diphtheria 4.1 Background 4.2 Epidemiology and risk groups 4.3 Diphtheria vaccine 4.3.1 Vaccine efficacy 4.3.2 Vaccine safety 4.4 Recommendations for diphtheria pre-exposure prophylaxis in HIV-infected adults 4.5 Post-exposure prophylaxis 4.6 Auditable outcomes 5.0 Haemophilus influenzae serotype b 5.1 Background 5.2 Epidemiology and risk groups 5.3 Hib vaccine 5.3.1 Vaccine efficacy 5.3.2 Vaccine safety 5.4 Recommendations for H. influenzae pre-exposure prophylaxis in HIV-infected adults 5.5 Post-exposure prophylaxis 5.6 Auditable outcomes 6.0 Hepatitis A 6.1 Background 6.2 Epidemiology and risk groups 6.3 Hepatitis A vaccine 6.3.1 Vaccine efficacy 6.3.2 Vaccine safety 6.4 Human normal immunoglobulin 6.5 Recommendations for hepatitis A pre-exposure prophylaxis in HIV-infected adults 6.6 Post-exposure prophylaxis 6.7 Recommendations for hepatitis A post-exposure prophylaxis in HIV-infected adults 6.8 Auditable outcomes 7.0 Hepatitis B 7.1 Background 7.2 Epidemiology and risk groups 7.3 Hepatitis B vaccine 7.3.1 Vaccine efficacy 7.3.2 Vaccine safety 7.4 Recommendations for hepatitis B pre-exposure prophylaxis in HIV-infected adults 7.5 Post-exposure prophylaxis *Anna Maria Geretti, Royal Free Hospital, London; Gary Brook, Central Middlesex Hospital, London; Claire Cameron, Health Protection Agency, Colindale; David Chadwick, James Cook University Hospital, Middlesbrough; Robert S Heyderman, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Eithne MacMahon, Guy’s and St Thomas’ NHS Foundation Trust, London; Anton Pozniak, Chelsea and Westminster Hospital, London; Mary Ramsay, Health Protection Agency, Colindale; M Schuhwerk, Mortimer Market Centre, London.