Marta Boffito

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.

British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015

Writing Group Duncan Churchill, Chair, Royal Sussex County Hospital, Brighton, UK Laura Waters, Vice Chair, Mortimer Market Centre, London, UK Nadia Ahmed, Mortimer Market Centre, London, UK Brian Angus, University of Oxford, UK Marta Boffito, Chelsea and Westminster Hospital, London, UK Mark Bower, Chelsea and Westminster Hospital, London, UK David Dunn, University College London, UK Simon Edwards, Central and North West London NHS Foundation Trust, UK Carol Emerson, Royal Victoria Hospital, Belfast, UK Sarah Fidler, Imperial College School of Medicine at St Mary’s, London, UK †Martin Fisher, Royal Sussex County Hospital, Brighton, UK Rob Horne, University College London, UK Saye Khoo, University of Liverpool, UK Clifford Leen, Western General Hospital, Edinburgh, UK Nicola Mackie, Imperial College Healthcare NHS Trust, London, UK Neal Marshall, Royal Free Hospital NHS Trust, London, UK Fernando Monteiro, UK-CAB Mark Nelson, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK

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

Protein Binding in Antiretroviral Therapies

There is marked variability in the extent to which the three classes of antiretroviral (ARV) drugs bind to plasma proteins (<5 to >99%). Protease inhibitors (PIs), with the exception of indinavir, are more than 90% protein bound, mainly to alpha1-acid glycoprotein (AAG). Efavirenz, a nonnucleoside reverse transcriptase inhibitor (NNRTI), is more than 99% bound, mainly to albumin. Nucleoside reverse transcriptase inhibitors (NRTIs) are not highly protein bound. The pharmacological activity of ARV drugs is dependent on unbound drug entering cells that harbor the human immunodeficiency virus (HIV). There has been concern that changes in protein binding could impact on antiviral activity and management. However, for PIs and NNRTIs, and for many drugs given orally, altered plasma binding would not be expected to influence the average exposure to unbound (active) drug after chronic oral dosing. Nevertheless, there will be a change in the relationship between total and unbound concentrations that will be important if, as part of therapeutic drug monitoring, the total rather than the unbound drug is measured. Measuring drug concentrations that are needed to inhibit different HIV strains (wild type and drug resistant) in vitro could also cause confusion because most methods employ bovine serum in the assay medium, and unbound concentrations are not directly measured. Estimating unbound drug concentrations in human plasma and in incubation media can be highly method dependent and thus may affect the calculated IC50 (the concentration of drug that results in 50% inhibition of viral replication). Because inhibitory quotients (IQs = C(trough)/IC50) are becoming part of pharmacokinetic/pharmacodynamic (PK/PD) analyses of clinical trial data, the strengths and weaknesses of the methods used for the determination of unbound drug concentration in plasma and in vitro systems--ultracentrifugation, ultrafiltration, and equilibrium dialysis--need to be understood. Consensus on standard procedures must be reached. In June 2002, a panel of experts assembled by the Forum for Collaborative HIV Research met in Washington, DC, to review the basic principles of protein binding of ARV drugs, and to discuss the impact that changes in plasma protein binding may have on the PKs and activity of ARV drugs as well as on therapeutic drug monitoring. The purpose of the meeting was to discuss the following topics: (1) basic principles of protein binding and how changes in binding can impact on drug PKs and drug exposure in vivo, (2) variability in plasma protein binding among patients taking ARV drugs, (3) the impact of HIV infection and concomitant diseases on the extent of plasma protein binding, (4) the likelihood of clinically relevant drug interactions at the level of plasma protein binding, (5) the evidence that measuring unbound concentrations of ARV drugs in the plasma of patients gives more meaningful information than total drug concentration and, therefore, should be considered in routine therapeutic drug monitoring of ARV agents, (6) optimal method(s) for measuring the unbound concentration of drugs in vitro (for IC50 determination) and in vivo, and (7) future studies that need to be considered to fully understand the importance of plasma protein binding in therapeutic drug monitoring. This report summarizes the topics discussed at this meeting. It guides the reader through the discussions that allowed the panel to formulate a series of statements regarding the significance of plasma protein binding of ARV drugs when studied in vitro and in vivo. The roundtable participants also identified research priorities that are important for understanding the sources of inter- and intraindividual variability in protein binding in patients. These include obtaining data on unbound as well as on total concentrations in PK studies; looking at variants of AAG and whether they differ in binding affinity; and emphasizing the importance of developing a standard procedure for drug susceptibility assays used to determine IC50 values.

Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance.

Background:Cumulative antiretroviral exposure can result in multiclass HIV drug resistance. Experimental antiretroviral agents offer limited therapeutic benefit as resistance quickly develops after their introduction as a sole new agent. Objective:To assess the pharmacokinetic profile, safety and virological response of two novel investigational antiretroviral agents when used in combination in HIV-1-infected subjects with multidrug-resistant virus. Methods:HIV-1-infected subjects, with current virological failure on a stable antiretroviral regimen with no viable treatment options were assigned to a regimen comprising two new investigational agents, etravirine, a novel nonnucleoside reverse transcriptase inhibitor, and darunavir, a novel protease inhibitor, plus nucleoside reverse transcriptase inhibitors (and enfuvirtide in selected patients) for 24 weeks. Virological, immunological and safety parameters were collected. Detailed pharmacokinetic assessments of darunavir and etravirine were determined on days 7 and 28. Results:Follow up of 24 weeks was achieved by 10/12 patients. Median reduction in HIV RNA was 2.7 log10 copies/ml (range, 2.3–3.9) and increase in CD4 lymphocytes was 113 cells/μl (range, 41–268). HIV RNA was < 40 copies/ml in nine. No serious adverse events were recorded. Plasma exposure to darunavir was similar to historic control data and exposure to etravirine similar to historic data when etravirine was administered with a boosted protease inhibitor. Conclusion:This first study to assess the use of etravirine and darunavir in HIV-1-infected subjects with no treatment options showed highly effective virological and immunological responses over 24 weeks of therapy with no new safety concerns or unexpected pharmacokinetic interactions.

Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial

Objective:To compare the safety and efficacy of two once-daily antiretroviral regimens containing lamivudine (3TC) or tenofovir disoproxil fumarate (TDF), each administered with didanosine (ddI) and efavirenz (EFV) as initial therapy to HIV-1-infected subjects. Methods:Single centre, randomized (1: 1), open-label study in antiretroviral-naive, HIV-infected adults. Subjects commenced either 3TC/ddI/EFV (3TC group) or TDF/ddI/EFV (TDF group). Safety, Medication Event Monitoring System (MEMScap) and plasma EFV concentration monitoring was performed over the study period. Comparisons between groups were assessed using χ2 test and linear regression analysis was used to assess the relationship between EFV concentrations and virological response. Results:Seventy-seven subjects were enrolled prior to recruitment being suspended, 36 to the 3TC group and 41 to the TDF group. Intention-to-treat analysis in which last observation carried forward (LOCF) found the mean viral log10 load [95% confidence interval (CI)] at weeks 4 and 12 to be 2.67 (2.47–2.87) and 1.83 (1.74–1.92) for the 3TC group and 2.75 (2.45–3.05) and 2.28 (1.96–2.6) for the TDF group (P = 0.013). Emergence of resistance occurred in five of 41 (12.2%) subjects in the TDF group up to week 12 compared with none of 36 in the 3TC group, (P < 0.05); these five subjects shared similar baseline characteristics (CD4+ cell counts < 200 × 106 cells/l and HIV-1 RNA > 100 000 copies/ml). Despite MEMScap monitoring showing > 99% adherence in all subjects, among the five failures, three had low EFV concentrations. Conclusion:TDF/ddI/EFV as initial therapy appears to have diminished efficacy in subjects with CD4 < 200 × 106 cells/l and viral load > 100 000 copies/ml. Treatment failure with resistance was not attributable to baseline resistance, efavirenz exposure or poor adherence.

Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen

Objective: To determine the pharmacokinetics of saquinavir hard-gel capsules/ ritonavir/atazanavir co-administered once daily at 1600/100/300 mg in HIV-infected individuals. Methods: Eighteen patients receiving saquinavir/ritonavir switched to 1600/100 mg once daily a minimum of 3 days before the study. On study day 1, levels of saquinavir and ritonavir were determined over 24 h. Atazanavir (300 mg once daily) was then added to the regimen. On day 11, a pharmacokinetic analysis was performed. Atazanavir was discontinued on day 32. Drug concentrations were measured by high-pressure liquid chromatography–tandem mass spectrometry. Geometric mean ratios (GMR) and 95% confidence intervals (CI) were used to compare saquinavir and ritonavir pharmacokinetic parameters, with and without atazanavir. A safety analysis was performed at screening, days 1, 11, 32 and follow-up. Results: After the addition of atazanavir, statistically significant increases in saquinavir trough plasma concentration (Ctrough GMR, 95% CI 2.12, 1.72–3.50), maximum plasma concentration (Cmax 1.42, 1.24–1.94), area under the plasma concentration–time curve from 0–24 h (AUC0–24 1.60, 1.35–2.43) and ritonavir Cmax (1.58, 1.32–2.08), AUC0–24 (1.41, 1.22–1.74) were observed. The pharmacokinetics of atazanavir compared with those obtained in patients receiving atazanavir/ritonavir without saquinavir. Four patients developed scleral icterus and two jaundice. Total and unconjugated bilirubin increased approximately fivefold during atazanavir therapy. Conclusion: The addition of atazanavir to saquinavir/ritonavir increased saquinavir Ctrough, Cmax and AUC0–24 by 112, 42 and 60%. Ritonavir Cmax and AUC0–24 increased by 34 and 41%. The regimen was well tolerated, with no significant change in laboratory parameters, except for the occurrence of hyperbilirubinemia.

The effect of HAART in 254 consecutive patients with AIDS-related Kaposi's sarcoma.

Objective:A prospective cohort study was performed to evaluate the clinical outcomes of patients with histologically confirmed AIDS-related Kaposis sarcoma diagnosed since the introduction of HAART. Methods:Two hundred and fifty-four consecutive patients (96% men) diagnosed with Kaposis sarcoma between 1996 and 2008 are included. Clinicopathological and treatment details were prospectively collected. The median follow-up is over 4 years and maximum 12 years. Results:The mean age at Kaposis sarcoma diagnosis was 39 years and average duration of known HIV seropositivity was 4 years. At Kaposis sarcoma diagnosis, only 19% patients were on HAART and only 7% patients had an undetectable plasma HIV viral load. Seventy-nine (31%) patients had AIDS clinical Trial Group stage T1 disease at Kaposis sarcoma diagnosis and 122 (48%) had AIDS clinical Trial Group stage I1 disease (CD4 cell count < 150 cells/μl). Nodular grade Kaposis sarcoma represented 28% of the tumours and was significantly associated with black African ethnicity and AIDS clinical Trial Group T1 stage disease. The overall 5-year survival is 89% (95% confidence interval 84–93). One hundred and sixty-three patients were treated with HAART alone for T0 stage Kaposis sarcoma; only one died of Kaposis sarcoma and only 37 (22%) required chemotherapy, giving a systemic treatment-free survival at 5 years of 74% (95% confidence interval 67–82) and the overall survival at 5 years is 91% (95% confidence interval 87–95). Conclusion:The high success rate of HAART in a large cohort of AIDS–Kaposis sarcoma patients over a prolonged period of follow-up will reassure patients and clinicians that this is a well tolerated and effective approach to stage T0 Kaposis sarcoma.

Pharmacokinetics and pharmacodynamics of drug interactions involving rifampicin, rifabutin and antimalarial drugs

Malaria and tuberculosis (TB) are two major global diseases mostly affecting the developing countries. Their treatment is often complex because of the drugs used, multidrug resistance, drug interactions and logistic problems such as drug availability and access. Patients are treated for TB for a minimum of 6 months and may concomitantly develop and be treated for malaria, especially during the rainy season. Rifampicin, a standard component of combination regimens for treating TB, is a potent inducer of hepatic cytochrome and other metabolic enzymes and is able to influence the pharmacokinetics of many drugs. Rifabutin, another rifamycin used less frequently than rifampicin, can also interact with drugs metabolized through the hepatic cytochromes. The mechanisms of any interaction of rifamycins with drugs used in malaria are not well defined. To complicate matters, acute malaria also plays a role in the pharmacokinetics and pharmacodynamics of drugs (i.e. quinine). The aim of this paper is to review known and potential drug-drug interactions between rifampicin, rifabutin and antimalarial drugs.

Pharmacokinetics, Efficacy, and Safety of Darunavir/Ritonavir 800/100 mg Once-Daily in Treatment-Naïve and -Experienced Patients

Abstract Darunavir is a new protease inhibitor (PI) with in vitro activity against wild-type and PI-resistant HIV; it is used with the pharmacokinetic booster ritonavir. The currently approved dose of darunavir/ritonavir is 600/100 mg twice-daily, licensed for treatment-experienced patients. However, during the clinical development of darunavir, a range of once-daily and twice-daily doses of darunavir/ritonavir were evaluated. The relatively long terminal elimination plasma half-life of darunavir (15 hours) supports once-daily dosing. In treatment-naïve patients, the ARTEMIS trial has shown high rates of HIV RNA suppression for darunavir-ritonavir at the 800/100 mg once-daily dose (84% with HIV RNA <50 copies/mL at Week 48) versus a control arm of lopinavir/ritonavir (78% with HIV RNA <50 copies/mL). In a population pharmacokinetic substudy, darunavir 24-hour minimum plasma concentration levels remained above the predefined EC50 of 55 ng/mL for all 335 patients evaluated in the ARTEMIS trial. Once-daily darunavir/ritonavir has also been evaluated in treatment-experienced patients in the TMC114-C207 proof-of-principle trial and the POWER 1 and 2 trials. For the overall POWER trial population, with significant baseline resistance to PIs, the rates of HIV RNA suppression <50 copies/mL at Week 24 for darunavir/ritonavir 800/100 mg once-daily were lower than for the 600/100 mg twice-daily dosage (31% vs. 47%, respectively). However, for patients with no genotypic darunavir resistance-associated mutations at baseline, rates of HIV RNA suppression were 62% and 67% for the 800/100 mg once-daily and 600/100 mg twice-daily doses. The current evidence from clinical trials of darunavir/ritonavir supports the efficacy of the 800/100 mg once-daily dose for treatment-naïve patients and further evaluation for treatment-experienced patients with no genotypic resistance to darunavir.