Pharmacokinetics and safety of twice-daily ritonavir-boosted atazanavir with rifampicin.

BACKGROUND: Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin. METHODS: DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with HIV on atazanavir/ritonavir-based ART in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg BID with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data was interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L. RESULTS: We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, while 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported an SAE, or experienced rebound viraemia. CONCLUSIONS: Twice daily atazanavir/ritonavir during rifampicin co-administration was well-tolerated and achieved plasma concentrations above the target.

An effective strategy to diagnose HIV infection: findings from a national audit of HIV partner notification outcomes in sexual health and infectious disease clinics in the UK.

OBJECTIVES: Partner notification (PN) is a key public health intervention in the control of STIs. Data regarding its clinical effectiveness in the context of HIV are lacking. We sought to audit HIV PN outcomes across the UK. METHODS: All UK sexual health and HIV services were invited to participate. Clinical audit consisted of retrospective case-note review for up to 40 individuals diagnosed with HIV per site during 2011 (index cases) and a review of PN outcomes for up to five contacts elicited by PN per index case. RESULTS: 169/221 (76%) clinical services participated (93% sexual health/HIV services, 7% infectious diseases/HIV units). Most (97%) delivered PN for HIV. Data were received regarding 2964 index cases (67% male; 50% heterosexual, 52% white). PN was attempted for 88% of index cases, and outcomes for 3211 contacts were audited (from an estimated total of 6400): 519 (16%) were found not to be at risk of undiagnosed HIV infection, 1399 (44%) were informed of their risk and had an HIV test, 310 (10%) were informed of the risk but not known to have tested and 983 (30%) were not informed of their risk of HIV infection. Of 1399 contacts tested through PN, 293 (21%) were newly diagnosed with HIV infection. Regular partners were most likely to test positive (p<0.001). CONCLUSIONS: HIV PN is a highly effective diagnostic strategy. Non-completion of PN thus represents a missed opportunity to diagnose HIV in at-risk populations. Vigorous efforts should be made to pursue PN to identify people living with, and at risk of, HIV infection.

Condomless sex in HIV-diagnosed men who have sex with men in the UK: prevalence, correlates, and implications for HIV transmission.

OBJECTIVE: HIV transmission is ongoing among men who have sex with men (MSM) in the UK. Sex without a condom (condomless sex, CLS) is the main risk factor. We investigated the prevalence of and factors associated with types of CLS. METHODS: Cross-sectional questionnaire study in UK HIV clinics in 2011/2012 (ASTRA). MSM diagnosed with HIV for ≥3 months reported on anal and vaginal sex, CLS with HIV-serodifferent partners (CLS-D) and CLS with HIV-seroconcordant (CLS-C) partners in the previous 3 months. Mutually exclusive sexual behaviours were as follows: (1) Higher HIV risk CLS-D (not on antiretroviral therapy (ART) or clinic-recorded viral load(VL) >50 c/mL), (2) Other CLS-D, (3) CLS-C without CLS-D, (4) Condom-protected sex only and (5) No anal or vaginal sex. Associations were examined of sociodemographic, HIV-related, lifestyle, and other sexual measures with the five categories of sexual behaviour. We examined the prevalence of higher HIV risk CLS-D incorporating (in addition to ART and VL) time on ART, ART non-adherence, and recent sexually transmitted infections (STIs). RESULTS: Among 2189 HIV-diagnosed MSM (87% on ART), prevalence of any CLS in the past 3 months was 38.2% (95% CI 36.2% to 40.4%) and that of any CLS-D was 16.3% (14.8%-17.9%). The five-category classification was as follows: (1) Higher HIV risk CLS-D: 4.2% (3.5% to 5.2%), (2) Other CLS-D: 12.1% (10.8% to 13.5%), (3) CLS-C without CLS-D: 21.9% (20.2% to 23.7%), (4) Condom-protected sex only: 25.4% (23.6% to 27.3%) and (5) No anal or vaginal sex: 36.4% (34.3% to 38.4%). Compared with men who reported condom-protected sex only, MSM who reported any CLS in the past 3 months had higher prevalence of STIs, chemsex-associated drug use, group sex, higher partner numbers, and lifetime hepatitis C. Prevalence of higher HIV risk CLS-D ranged from 4.2% to 7.5% according to criteria included. CONCLUSION: CLS was prevalent among HIV-diagnosed MSM, but CLS-D with higher HIV transmission risk was overall low. CLS-D is no longer the most appropriate measure of HIV transmission risk behaviour among people with diagnosed HIV; accounting for VL is important.

Non-Disclosure of HIV Status and Associations with Psychological Factors, ART Non-Adherence, and Viral Load Non-Suppression Among People Living with HIV in the UK.

Disclosure of HIV status to family, friends, and a stable partner may be linked to improved health outcomes for people living with HIV. This study assessed whether non-disclosure is associated with psychological symptoms, non-adherence to antiretroviral therapy (ART), and viral load (VL) non-suppression. A total of 3258 HIV-diagnosed individuals in the UK completed the confidential ASTRA study questionnaire (2011-2012). Participants reported whether they told anyone they had HIV; to which confidant(s) (friends, family, work colleagues, stable partner) and to what extent (none, some, most/all). The prevalence and factors associated with non-disclosure were assessed. Associations between non-disclosure and the following factors were established using modified Poisson regression with adjustment for socio-demographic factors (gender, age group, ethnicity), HIV-related factors (time since HIV diagnosis, ART status), and clinic: low social support (score ≤ 12 on modified Duke-UNC FSSQ); depression and anxiety symptoms (≥10 on PHQ-9 and GAD-7 respectively); self-reported ART non-adherence in past 2 weeks/3 months; VL non-suppression (clinic-recorded VL > 50 copies/mL among those who started ART ≥ 6 months ago). Among 3233 participants with disclosure data, the prevalence of non-disclosure to anyone was 16.6 % (n/N = 61/367) among heterosexual men, 15.7 % (98/626) among women, and 5.0 % (113/2240) among MSM. MSM were more likely to disclose to some/all friends compared to family (85.8 vs. 59.9 %) while heterosexuals were less likely to disclose to friends than family (44.1 vs. 61.1 % for men, 57.5 vs. 67.1 % for women). Among 1,631 participants with a stable partner, non-disclosure to a stable partner was 4.9 % for MSM, 10.9 % for heterosexual men, and 13.0 % for women. In adjusted analyses, older age (≥60 years), non-white ethnicity, more recent HIV diagnosis, and not having a stable partner were significantly associated with overall non-disclosure for MSM and heterosexual individuals. The prevalence of low social support was 14.4 %, of depression and anxiety symptoms 27.1 and 22.0 %, respectively, of ART non-adherence 31.8 %, and of viral load non-suppression on ART 9.8 %. There was no evidence that non-disclosure overall (versus disclosure to anyone) was associated with low social support, depression or anxiety symptoms, ART non-adherence or VL non-suppression among MSM or heterosexual individuals. However, compared to MSM who disclosed to 'none' or 'some' friends and family, MSM who disclosed to 'most or all' of their friends and family were more likely to have symptoms of depression (adjusted PR = 1.4, 95 % CI 1.2-1.7), anxiety (1.3, 1.1-1.6), and to report ART non-adherence (1.3, 1.1-1.5). In this large multicentre study of people living with HIV in the UK, non-disclosure was overall low, but higher for heterosexual individuals compared to MSM. Non-disclosure was not associated with higher prevalence of adverse health measures.

Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment-naive adults infected with HIV-1 through 48 weeks of treatment.

This 96-week, randomized, open-label study was designed to assess the efficacy and safety of two single-tablet regimens in treatment naïve HIV-1-infected adults: rilpivirine (RPV) + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and efavirenz (EFV) + FTC/TDF. Assessments included patient-reported Medication Adherence Self-Report Inventory, SF-12v2 Quality of Life assessment, HIV Treatment Satisfaction Questionnaire, and HIV Symptom Index Questionnaire through Week 48. Additional evaluations included study drug discontinuations due to treatment-emergent adverse events (TEAEs). A total of 786 participants (n=394 RPV/FTC/TDF, n=392 EFV/FTC/TDF) were included. Fewer RPV/FTC/TDF-treated than EFV/FTC/TDF-treated participants discontinued study drug due to TEAEs (2.5% vs. 8.7%), with 41% (14/34) TEAE-related discontinuations in the EFV/FTC/TDF group occurring within the first four weeks of treatment. Treatment adherence and satisfaction remained high through Week 48 and quality of life improved from baseline in both groups. There were no significant between-group differences in virologic success (HIV-1 RNA <50 copies/mL) regardless of adherence (<95% or ≥95%). Significant between-group differences favouring RPV/FTC/TDF were observed for the HIV SIQ symptoms of difficulty falling or staying asleep (p = .022) and diarrhea or loose bowel movements (p = .002). In conclusion, 48-week treatment with RPV/FTC/TDF or EFV/FTC/TDF was associated with high adherence, high treatment satisfaction, and improved quality of life. TEAE-related discontinuations and patient-reported symptoms indicate that RPV/FTC/TDF may be somewhat better tolerated than EFV/FTC/TDF.

Lopinavir/ritonavir single agent therapy as a universal combination antiretroviral therapy stopping strategy: results from the STOP 1 and STOP 2 studies.

OBJECTIVES: We designed two different studies to evaluate two different combination antiretroviral therapy (cART) stopping strategies namely a 'staggered stop' approach (STOP 1 study) and a 'protected stop' approach (STOP 2 study) to find the best 'universal stop' strategy. PATIENTS AND METHODS: Patients who stopped cART for any reason were recruited. In STOP 1, 10 patients on efavirenz continued dual nucleos(t)ide reverse transcriptase inhibitors (NRTIs) for 1 week after discontinuing efavirenz. Efavirenz concentrations were measured weekly for up to 3 weeks. In STOP 2, 20 patients stopped their cART and replaced it with two tablets of lopinavir/ritonavir (Kaletra) (100/50 mg) twice daily for 4 weeks. Lopinavir, efavirenz, nevirapine and tenofovir concentrations were measured weekly for up to 4 weeks. Virological and resistance testing were performed. RESULTS: In STOP 1 five patients still had efavirenz present (median t(1/2)=148.4 h) 3 weeks after stopping. In STOP 2, 15/20 patients had a viral load (VL) of <40 copies/mL and 3/20 patients had a reduction in VL by 4 weeks. Six patients opted not to stop lopinavir/ritonavir and still had <40 copies/mL at week 8. Week 1-4 median trough lopinavir concentrations were well above the EC(95). Six patients still had detectable concentrations of original cART persisting for >1 week after stopping. No patients developed new resistance mutations. CONCLUSIONS: Plasma efavirenz concentrations can persist up to 3 weeks after patients stop efavirenz-containing regimens. This suggests a strategy of stopping efavirenz only 1 week before NRTIs may not be long enough for some individuals. The use of lopinavir/ritonavir monotherapy for a 4 week period may be an alternative pharmacologically and virologically effective universal stopping strategy which warrants further investigation.

Neurological complications in HIV.

HIV is neuroinvasive with early involvement of the nervous system and has the potential to cause disease at any site of the neuro-axis during the evolution from seroconversion to late stage HIV. Disease may result from direct viral infection, indirect immune-deficiency driven opportunistic infections, AIDS-defining cancers, antiretroviral (ARV) drug therapy, or less well elucidated associations, such as vascular events (Table 1). Recognition of each of these is paramount in the prevention or attenuation of long-term morbidity. Though the epidemiology of neurological disease has altered substantially since the arrival of combination antiretroviral therapy (cART), with reduced incidence and improved survival, the spectrum of central nervous system (CNS) diseases has remained relatively unchanged. Despite available treatment options, mortality remains high and the morbidity significant. CNS diseases can result in long hospital stays, reduced quality of life and marked disability. The majority of disease occurs in the advanced stages of HIV infection where immunosuppression is the predominant influence. Diagnosis can prove challenging as presentation is often atypical and there can be significant neurological involvement with limited evidence of disease. Multiple aetiologies can co-exist and investigations may yield unexpected results, rendering interpretation difficult. Paradoxically, cART may also alter the way CNS disease manifests and unmask opportunistic infections or cause clinical representation of the opportunistic infections, when it represents immune reconstitution syndrome (IRS). Clinical assessment, imaging (typically magnetic resonance imaging (MRI)) and cerebral spinal fluid (CSF) sampling remain the chief diagnostic tools. This conference summary reviews these differing aspects.

Tumefactive demyelination-an unusual neurological presentation of HIV.

We describe 3 individuals infected with human immunodeficiency virus with unusual focal brain syndromes; magnetic resonance imaging revealed "open-ring" pattern space occupying lesions. After deterioration while the patients were receiving anti-Toxoplasma therapy, brain biopsy was performed, which revealed aggressive demyelination consistent with tumefactive demyelination. Treatment with high-dose steroids resulted in complete recovery in all cases.

Opportunistic infections in HIV disease.

Since the emergence of the HIV pandemic in the 1980s, there have been great advances in the treatment of HIV through potent and effective antiretroviral therapy. This has led to HIV-infected individuals presenting with fewer opportunistic infections and, subsequently, leading longer lives in better health. Nevertheless, there are HIV-positive people in both high- and low-resource settings who may present late with marked immunodeficiency or have no access to adequate medical care and antiretroviral therapy. Within these populations, opportunistic infections rate still remain unacceptably high. This article outlines the variety of opportunistic infections that can be seen in clinical practice, and highlights the way in which these infections can be pre-empted, diagnosed and treated according to best practice guidelines.

UK national audit of sexual health care for people with HIV infection: clinic policies.

A national audit of the sexual health care for people with HIV infection (PWHIV) was conducted in genitourinary medicine clinics and other clinics providing care for PWHIV in the UK in the summer of 2006. Data were aggregated by region and clinic, allowing practice to be compared between regions, as well as to national averages and against various guidelines. In this, the first of two papers, clinics were surveyed on their local policies. In total, 126 clinics participated. Only 38 clinics (30%, regional range 0-60%) had written local care pathways on management of sexually transmitted infection in PWHIV, while 73 (58, 20-100%) had unwritten policies. This compares with the national standard that 100% of service providers should be able to provide documentation of local care pathways for sexually transmitted diseases in people with HIV. Clinics should consider creating policies especially where standards are not being met.

UK national audit of sexual health care for people with HIV infection: case-notes audit.

The case-notes of 3210 patients with HIV infection were audited. A sexual history was documented within four weeks before or after initial HIV diagnosis in 69% of cases (regional range 45-84%), and in the six months before attendance during the audit interval in 34% (12-53%). An offer of tests for sexually transmitted infections was documented within four weeks before or after HIV diagnosis in 58% (30-83%), and in the prior six months in 28% (14-47%). Syphilis serology was offered in the previous three months to 45% (14-100%) of cases resident in syphilis outbreak areas and to 25% (7-62%) of other cases. Hepatitis B testing was performed for 98% (95-100%) of cases and for hepatitis C, for 91% (79-100%). Cervical cytology results in the past year were documented for 73% (43-94%) of eligible women. Considerable inter-regional variation in performance exists. Interventions are needed to improve the sexual health care of people with HIV infection.

Pseudohepatic tumour associated with secondary syphilis in an HIV-positive male.

Inflammatory pseudohepatic tumours are unusual tumour-like conditions which can easily be mistaken for malignant lesions or liver abscesses. Patients usually present with fever, abdominal pain and loss of weight. The aetiology is unclear but the predominant inflammatory pattern of pathology and the associated systemic reactions suggest an underlying infectious agent. In the majority, microorganisms are not detected. As even routine imaging procedures usually fail to distinguish hepatic pseudotumours from liver neoplasms, biopsy is the definitive means of diagnosis. Until now, no case of pseudohepatic tumour has been reported as being associated with secondary syphilis. We believe secondary syphilis is the cause of this pseudohepatic tumour in our HIV-positive male.

Nevirapine use in HIV-1-infected children.

OBJECTIVES: To evaluate the safety, efficacy, and clinical, virological, and immunological responses in HIV-1-infected children receiving nevirapine as part of combination antiretroviral therapy (ART). METHODS: A review of case notes of all HIV-1-infected children 96 weeks after starting nevirapine, under a national compassionate access scheme between August 1997 and March 1999 in the UK. Nevirapine was dosed according to the manufacturer's guidelines. RESULTS: Seventy-four children (36 boys, 28 naive to ART) were enrolled, with a median age of 5.2 years, viral load of 5.1 log copies/ml and CD4 lymphocyte count of 13.5%. The liquid formulation and tablets of nevirapine were well tolerated. The proportions of patients achieving undetectable viral load levels at weeks 12, 24, 48 and 96 were 30, 40, 36 and 33%, respectively (intention-to-treat analysis). Of children not on a protease inhibitor who received more than 300 mg/m2/day of nevirapine, 60% had undetectable viral loads at week 96, compared with 17% on recommended doses. Outcomes were similar for patients receiving nevirapine once or twice daily. CD4 cell count percentages increased significantly, with median values sustained above 25% by week 48 onwards. Z-scores for weight and height increased significantly during 96 weeks of treatment. Rash occurred in 20%, of which four (5%) were severe. There were no cases of Stevens-Johnson syndrome. CONCLUSION: Nevirapine was mostly well tolerated, and was associated with encouraging clinical and immunological responses. Virological responses in this cohort support the use of nevirapine doses greater than 300 mg/m2/day, which is higher than currently recommended by the manufacturers.

Drug resistance genotypes predict response to amprenavir-containing regimens in highly drug-experienced HIV-1-infected patients.

We have undertaken a study of virological responses to amprenavir-containing antiretroviral regimens, during the expanded access programme within the UK. Ninety-five HIV-1-infected patients were included for which virological and immunological follow-up was available for 75, and baseline drug resistance data available for 51. These were highly drug-experienced patients, having previously received a median of nine antiviral drugs, within all available classes. Eighty-eight percent of patients had a virological response to the new regimen, with a median maximal decline of 1.45 log10 copies/ml, and 34% of patients reached <400 copies/ml on treatment. Although 68% of patients with resistance data had protease inhibitor resistance mutations, only 10% patients had key amprenavir resistance mutations, and virological response was predicted by the number of active drugs utilized in the amprenavir-containing regimen, as determined by the baseline genotypic resistance test. Other independent predictors of viral load decline were a higher baseline viral load and fewer previous antiviral drugs. We conclude that amprenavir can contribute to antiviral efficacy in salvage regimens, and that resistance testing may help to optimize its use in this scenario. New formulations of amprenavir, together with boosted regimens, may enhance the activity in the presence of protease inhibitor-resistant virus.

Pharmacokinetics of Telzir (fosamprenavir).

Fosamprenavir is a recently licensed protease inhibitor (PI) for the treatment of patients with HIV. It has potent antiviral activity when boosted by ritonavir and produces durable virological suppression when combined with other antiretroviral drugs. In addition, it is well tolerated with a good safety profile, and can be taken once or twice daily with no food restrictions. Trough plasma levels obtained with once or twice daily boosted fosamprenavir are above the mean protein-binding adjusted IC50 values for wild-type and PI-resistant virus. When given twice daily boosted, no significant pharmacokinetic (PK) interaction is seen with tenofovir, the nucleoside reverse transcriptase inhibitors (NRTIs), efavirenz or nevirapine, and there is no requirement for any dose adjustment. Interactions with other PIs are difficult to predict. A reduction in plasma amprenavir level is seen when fosamprenavir or amprenavir is combined with ritonavir-boosted lopinavir, saquinavir or tipranavir: reductions in lopinavir and saquinavir plasma levels are also seen. Various dosing strategies have been evaluated to overcome these negative interactions. With unboosted atazanvir, an increase in amprenavir levels is found. This article will focus on the pharmacokinetics of ritonavir-boosted fosampreanvir and review drug interactions with other antiretroviral (ARV) and non-ARV agents.