David Asboe

Hyperlactataemia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors.

ObjectiveTo evaluate the prevalence, outcome and possible risk factors for hyperlactataemia and lactic acidosis in HIV-positive persons receiving antiretroviral therapy. MethodsCross-sectional and longitudinal data from a prospectively collected clinical database. Associations with antiretroviral regimen, clinical and laboratory parameters were assessed using univariate and multivariate Coxs proportional hazards model. ResultsPatients naive to therapy and patients on current therapy for a minimum of 4 months were assessed. Median lactate was 1.1 mol/l in 253 untreated individuals and 1.4 mmol/l in 1239 patients stable on therapy for at least 4 months. At least two on-therapy samples were available for 750 of the 1239 individuals, taken a median 92 days apart. Lactate measurement showed a low positive predictive value of 38.9% but a high negative predictive value (98%) for normal values. Lactate was elevated ⩾ 2.4 mmol/l in 102 individuals on at least one occasion. In the multivariate Coxs proportional hazards model, no demographic characteristics were associated with hyperlactataemia. Didanosine-containing regimens doubled the relative hazard of hyperlacatæmia compared with those sparing didanosine. Abacavir-containing regimens reduced the hazard of hyperlactatæmia. Choice of thymidine analogue did not influence risk. Hyperlactatæmia was associated with acid–base disturbance. Use of didanosine and female sex were over-represented amongst nine patients with severe hyperlactataemia (> 5 mmol/l) or lactic acidosis. ConclusionsScreening of lactate is of limited use in asymptomatic individuals on antiretroviral therapy. Raised lactate represents part of a spectrum of lactate and acid–base disturbance that infrequently includes lactic acidosis. Didanosine appears associated with an increased risk of hyperlactataemia.

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

Increased numbers of acute hepatitis C infections in HIV positive homosexual men; is sexual transmission feeding the increase?

Although the principal mode of hepatitis C (HCV) transmission in the United Kingdom is injecting drug use (IDU), the risk for a third of infections is unknown.1 The contribution of sexual transmission between men who have sex with men (MSM) to the spread of hepatitis C is unclear, however evidence is accumulating that both co-infection with HIV2 and the presence of other sexually transmitted infections (STIs) facilitate sexual transmission of HCV.3 With the reported increases in unsafe sex and STIs in HIV positive MSM we questioned whether these circumstances may lead to an increase in the number of HCV infections. This study was undertaken to determine whether within our clinics, changes in the number of individuals being diagnosed with acute HCV infection were occurring and to ascertain risk factors for acquisition in these individuals. A case note review of all patients within the HIV and sexual health clinics of St Stephen’s Centre with diagnosed acute HCV infection between January …

Transmission of hepatitis C virus among HIV-positive homosexual men and response to a 24-week course of pegylated interferon and ribavirin.

Objective:To evaluate treatment outcome of acute hepatitis C virus (HCV) in HIV-positive individuals. Design:Open-label, prospective study conducted in London, January 1997-December 2003. Methods:Patients in whom acute HCV infection had been diagnosed had sequential HCV RNA levels measured at 0, 4, 12, 24, 32, and 48 weeks. If HCV RNA positive at 12 weeks, patients were offered pegylated interferon α-2b 1.5 μg/kg/wk and ribavirin 800-1200 mg/d for 24 weeks. Patients with increasing HCV RNA titers were offered treatment earlier. Results:Fifty male homosexuals with a mean age 37 years were identified: 44 from abnormal liver function test results, 4 from sexual contact with an HCV-positive partner, and 2 at HIV seroconversion. Overall, 12 individuals became HCV RNA negative spontaneously. This was significantly associated with high baseline median CD4+ count (P = 0.029), CD4+ count >500 cells/mm3 (P = 0.017), and lower HCV RNA titers (P = 0.017). Only 27 patients accepted treatment, 16 (59%) of whom reached sustained virologic response. This was associated with higher peak mean alanine aminotransferase (P < 0.001) and higher baseline CD4% (P = 0.041). Conclusions:Sustained virologic response rates in HIV-positive patients treated for acute HCV infection are lower than in HIV-negative subjects. Because a high percentage of individuals seroconvert spontaneously, treatment should be delayed until after 12 weeks.

Persistence of HIV-1 Transmitted Drug Resistance Mutations

There are few data on the persistence of individual human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) mutations in the absence of selective drug pressure. We studied 313 patients in whom TDR mutations were detected at their first resistance test and who had a subsequent test performed while ART-naive. The rate at which mutations became undetectable was estimated using exponential regression accounting for interval censoring. Most thymidine analogue mutations (TAMs) and T215 revertants (but not T215F/Y) were found to be highly stable, with NNRTI and PI mutations being relatively less persistent. Our estimates are important for informing HIV transmission models.

Time trends in drug resistant HIV-1 infections in the United Kingdom up to 2009: multicentre observational study.

Objective To evaluate whether the prevalence of HIV-1 transmitted drug resistance has continued to decline in infections probably acquired within the United Kingdom. Design Multicentre observational study. Setting All UK public laboratories conducting tests for genotypic HIV resistance as a part of routine care. Participants 14 584 patients infected with HIV-1 subtype B virus, who were first tested for resistance before receiving antiretroviral therapy between January 2002 and December 2009. Main outcome measure Prevalence of transmitted drug resistance, defined as one or more resistance mutations from the surveillance list recommended by the World Health Organization. Results 1654 (11.3%, 95% confidence interval 10.8% to 11.9%) patients had one or more mutations associated with transmitted HIV-1 drug resistance; prevalence was found to decline from 15.5% in 2002 to 9.6% in 2007, followed by a slight increase to 10.9% in 2009 (P=0.21). This later rise was mainly a result of increases in resistance to nucleos(t)ide reverse transcriptase inhibitors (from 5.4% in 2007 to 6.6% in 2009, P=0.24) and protease inhibitors (1.5% to 2.1%, P=0.12). Thymidine analogue mutations, including T215 revertants, remained the most frequent mutations associated with nucleos(t)ide reverse transcriptase inhibitors, despite a considerable fall in stavudine and zidovudine use between 2002 and 2009 (from 29.4% of drug regimens in 2002 to 0.8% in 2009, from 47.9% to 8.8%, respectively). Conclusions The previously observed decline in the prevalence of transmitted drug resistance in HIV-1 infections probably acquired in the UK seems to have stabilised. The continued high prevalence of thymidine analogue mutations suggests that the source of this resistance may be increasingly from patients who have not undergone antiretroviral therapy and who harbour resistant viruses. Testing of all newly diagnosed HIV-1 positive people should be continued.

The International Index of Erectile Function: Development of an Adapted Tool for Use in HIV-Positive Men Who Have Sex with Men

INTRODUCTION Erectile dysfunction is common in HIV-positive men who have sex with men (MSM). A standardized scale is needed to assess erectile function in clinical practice and research studies. AIM The International Index of Erectile Function (IIEF) is a widely accepted tool for assessing erectile function designed for heterosexual men. We modified the tool for MSM. We present an analysis of internal consistency of the questionnaire in an HIV-positive cohort. METHODS The adapted questionnaire included modified questions within each of the five domains of the IIEF: (i) erectile function, (ii) intercourse satisfaction, (iii) orgasmic function, (iv) sexual desire, and (v) overall satisfaction with sex. MSM at seven European HIV treatment centers completed the questionnaire. MAIN OUTCOME MEASURES Responses were analyzed for internal consistency using standardized Cronbachs alpha values within each of the five domains. A factor analysis was performed to confirm the domain structure of the questionnaire. RESULTS Data from 486 MSM were analyzed. The factor analysis supported the domain structure described. Questions about erectile function, orgasmic function, and sexual desire performed well, with Cronbachs alpha values of 0.82, 0.83, and 0.89, respectively. Questions concerning intercourse satisfaction were less consistent (Cronbachs alpha 0.55) because frequency of attempts at sexual intercourse did not correlate with other responses. Responses about satisfaction with sex with a regular partner diverged from satisfaction with overall sex life. Frequency of morning erections diverged from other aspects of erectile function, whereas erections with masturbation correlated better. CONCLUSIONS Internal consistency was high overall. This tool is suitable for HIV-positive MSM and can be used in screening, research, and monitoring treatment response.

Declining prevalence of HIV-1 drug resistance in antiretroviral treatment-exposed individuals in Western Europe

HIV-1 drug resistance represents a major obstacle to infection and disease control. This retrospective study analyzes trends and determinants of resistance in antiretroviral treatment (ART)-exposed individuals across 7 countries in Europe. Of 20 323 cases, 80% carried at least one resistance mutation: these declined from 81% in 1997 to 71% in 2008. Predicted extensive 3-class resistance was rare (3.2% considering the cumulative genotype) and peaked at 4.5% in 2005, decreasing thereafter. The proportion of cases exhausting available drug options dropped from 32% in 2000 to 1% in 2008. Reduced risk of resistance over calendar years was confirmed by multivariable analysis.

Persistence of Pseudomonas aeruginosa strains in respiratory infection in AIDS patients.

Objectives:To establish the clinical pattern of Pseudomonas aeruginosa respiratory infections in HIV-seropositive patients and to determine whether repeated isolation of the organism represents reinfection or recurrence and to assess whether common source, nosocomial infection occurred. Design and methods:Evaluation of the clinical pattern of P. aeruginosa respiratory infections by case note review and epidemiological characterization of P. aeruginosa by serotype determination and XbaI DNA macrorestriction analysis. Serum sensitivity testing of strains was performed to further define phenotypic characteristics of the isolated organisms. Results:Seventy-three per cent (29 out of 40) of individuals had P. aeruginosa isolated on two or more occasions in the setting of clinical respiratory infection. Overall, 85% had evidence of P. aeruginosa to within 2 months of study completion or death. Epidemiological characterization revealed persistence of unique single strains in 93% of individuals where multiple isolates were available for testing, whereas only two patients harboured a common strain. The serotype distribution of strains was similar to that reported from non-HIV-positive patients. Conclusions:Once established, eradication of P. aeruginosa from the respiratory tract of HIV-seropositive individuals with advanced immunosuppression is problematic and a chronic infective state appears common. There was no evidence of nosocomial transmission. Serotype loss and development of sensitivity to normal human serum were both observed and were highly correlated. This represents truncation of O-antigenic lipopolysaccharide on the cell surface of P. aeruginosa and may reflect progression to phenotypes commonly associated with chronic infection in other clinical settings such as cystic fibrosis.

Poly drug use, chemsex drug use, and associations with sexual risk behaviour in HIV-negative men who have sex with men attending sexual health clinics

BACKGROUND Recreational drug use and associated harms continue to be of significant concern in men who have sex with men (MSM) particularly in the context of HIV and STI transmission. METHODS Data from 1484 HIV-negative or undiagnosed MSM included in the AURAH study, a cross-sectional, self-completed questionnaire study of 2630 individuals from 20 sexual health clinics in the United Kingdom in 2013-2014, was analysed. Two measures of recreational drug use in the previous three months were defined; (i) polydrug use (use of 3 or more recreational drugs) and (ii) chemsex drug use (use of mephedrone, crystal methamphetamine or GHB/GBL). Associations of socio-demographic, health and lifestyle factors with drug use, and associations of drug use with sexual behaviour, were investigated. RESULTS Of the 1484 MSM, 350 (23.6%) reported polydrug use and 324 (21.8%) reported chemsex drug use in the past three months. Overall 852 (57.5%) men reported condomless sex in the past three months; 430 (29.0%) had CLS with ≥2 partners, 474 (31.9%) had CLS with unknown/HIV+ partner(s); 187 (12.6%) had receptive CLS with an unknown status partner. For polydrug use, prevalence ratios (95% confidence interval) for association with CLS measures, adjusted for socio-demographic factors were: 1.38 (1.26, 1.51) for CLS; 2.11 (1.80, 2.47) for CLS with ≥2 partners; 1.89 (1.63, 2.19) for CLS with unknown/HIV+ partner(s); 1.36 (1.00, 1.83) for receptive CLS with an unknown status partner. Corresponding adjusted prevalence ratios for chemsex drug use were: 1.38 (1.26, 1.52); 2.07 (1.76, 2.43); 1.88 (1.62, 2.19); 1.49 (1.10, 2.02). Polydrug and chemsex drug use were also strongly associated with previous STI, PEP use, group sex and high number of new sexual partners. Associations remained with little attenuation after further adjustment for depressive symptoms and alcohol intake. CONCLUSION There was a high prevalence of polydrug use and chemsex drug use among HIV negative MSM attending UK sexual health clinics. Drug use was strongly associated with sexual behaviours linked to risk of acquisition of STIs and HIV.