The Prevalence and Patterns of Menopausal Symptoms in Women Living with HIV.

Increasing numbers of women with HIV are experiencing menopause. We use data from a large, representative sample of women with HIV to describe the prevalence and clustering of menopausal symptoms amongst pre-, peri- and post-menopausal women using hierarchical agglomerative cluster analysis. Of the 709 women included, 21.6%, 44.9% and 33.6% were pre-, peri- and post-menopausal, respectively. Joint pain (66.4%) was the most commonly reported symptom, followed by hot flashes (63.0%), exhaustion (61.6%) and sleep problems (61.4%). All symptoms were reported more commonly by peri- and post-menopausal women compared to pre-menopausal women. Psychological symptoms and sleep problems clustered together at all menopausal stages. Somatic and urogenital symptom clusters emerged more distinctly at peri- and post-menopause. We recommend regular and proactive assessment of menopausal symptoms in midlife women with HIV, with an awareness of how particular patterns of symptoms may evolve over the menopausal transition.

Bone mineral density, kidney function, weight gain and insulin resistance in women who switch from TDF/FTC/NNRTI to ABC/3TC/DTG.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). We evaluated changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG). METHODS: We conducted a randomized controlled trial in which women aged ≥40 years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. The primary endpoint was change in total hip BMD measured by dual-energy X-ray absorptiometry at week 48. Secondary endpoints were changes in BMD of the lumbar spine and femoral neck and markers of bone turnover and kidney function up to week 48. We conducted exploratory analyses of weight gain, insulin resistance and metabolic syndrome. Primary and secondary endpoints were analysed by linear regression, with multiple imputation for missing time points. RESULTS: In all, 91 women [mean age = 50.4 (standard deviation [SD] = 6.6) years, median CD4 cell count = 600 (interquartile range: 479-800) cells/µL] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in total hip BMD (mean adjusted difference = 1%, P = 0.027) and lumbar spine BMD (3%, P = 0.002), with no change in specific markers of bone turnover or renal tubular function. Although participants in the ABC/3TC/DTG arm gained more weight (1.8 kg, P = 0.046), the switch strategy was not associated with reduced insulin sensitivity or new-onset metabolic syndrome. CONCLUSIONS: Switching from TDF/FTC/NNRTI to ABC/3TC/DTG resulted in improved BMD. Although weight gain was common in women who switched from TDF/FTC/NNRTI to ABC/3TC/DTG, we did not detect adverse effects on glucose homeostasis. Larger studies need to confirm these findings.

UK national clinical audit: management of pregnancies in women with HIV.

BACKGROUND: The potential for HIV transmission between a pregnant woman and her unborn child was first recognized in 1982. Since then a complex package of measures to reduce risk has been developed. This project aims to review UK management of HIV in pregnancy as part of the British HIV Association (BHIVA) audit programme. METHODS: The National Study of HIV in Pregnancy and Childhood (NSHPC), a population-based surveillance study, provided data for pregnancies with an expected delivery date from 1/1/13 - 30/6/14. Services also completed a survey on local management policies. Data were audited against the 2012 BHIVA pregnancy guidelines. RESULTS: During the audit period 1483 pregnancies were reported and 112 services completed the survey. Use of dedicated multidisciplinary teams was reported by 99% although 26% included neither a specialist midwife nor nurse. 17% of services reported delays >1 week for HIV specialist review of women diagnosed antenatally. Problematic urgent HIV testing had been experienced by 9% of services although in a further 49% the need for urgent testing had not arisen. Delays of >2 h in obtaining urgent results were common. Antiretroviral therapy (ART) was started during pregnancy in 37% women with >94% regimens in accordance with guidelines. Late ART initiation was common, particularly in those with a low CD4 count or high viral load. Eleven percent of services reported local policy contrary to guidelines regarding delivery mode for women with a VL <50 copies/mL at ≥36 weeks. According to NSHPC reports 27% of women virologically eligible for vaginal delivery planned to deliver by CS. CONCLUSIONS: Pregnant women in the UK are managed largely in accordance with BHIVA guidelines. Improvements are needed to ensure timely referral and ART initiation to ensure the best possible outcomes.

Quantification of hepatic FOXP3+ T-lymphocytes in HIV/hepatitis C coinfection.

Coinfection with HIV adversely impacts every stage of hepatitis C (HCV) infection. Liver damage in HCV infection results from host antiviral responses rather than direct viral pathogenesis. Despite depressed cellular immunity, coinfected patients show accelerated hepatic fibrosis compared with HCV monoinfected patients. This paradox is poorly understood. T-regulatory (Treg) cells (CD4+ and FOXP3+) are hypothesized to limit hepatic damage in HCV. Our hypothesis was that reduced frequency of hepatic Treg in HIV/HCV coinfection compared with HCV monoinfection may explain poorer outcomes. We quantified FOXP3+, CD4+, CD8+ and CD20+ cells in liver biopsies of 35 male subjects matched by age and ISHAK fibrosis score, 12 HIV monoinfected, 11 HCV monoinfected and 12 HIV/HCV coinfected. Cell counts were performed using indirect immunohistochemical staining and light microscopy. HIV/HCV coinfected subjects had fewer hepatic FOXP3+ (P = 0.031) and CD4+ cells (P = 0.001) than HCV monoinfected subjects. Coinfected subjects had more hepatic CD8+ cells compared with HCV monoinfected (P = 0.023), and a lower ratio of FOXP3+ to CD8+ cells (0.08 vs 0.27, P < 0.001). Multivariate analysis showed number of CD4+ cells controlled for differences in number of FOXP3+ cells. Fewer hepatic FOXP3+ and CD4+ cells in HIV/HCV coinfection compared with HCV monoinfection suggests lower Treg activity, driven by an overall loss of CD4+ cells. Higher number of CD8+ cells in HIV/HCV coinfection suggests higher cytotoxic activity. This may explain poorer outcomes in HIV/HCV coinfected patients and suggests a potential mechanism by which highly active antiretroviral therapy may benefit these patients.

Acute kidney injury as a presentation of primary renal diffuse large B-cell lymphoma in HIV.

We report a case of acute kidney injury due to primary renal diffuse large B-cell lymphoma, which developed after initiation of tenofovir-containing antiretroviral therapy in a 28-year-old HIV-positive man.

Pre-exposure prophylaxis for conception (PrEP-C) as a risk reduction strategy in HIV-positive men and HIV-negative women in the UK.

Couples wishing to have biological children when one partner is HIV positive and the other is HIV negative present clinicians with complex clinical, social and ethical considerations. We established two multidisciplinary pre-conception services for HIV-positive individuals and their partners. We report the first UK use of pre-exposure prophylaxis for conception (PrEP-C) as part of an overall risk reduction strategy. Couples were counselled and written informed consent for PrEP-C was obtained. Patient demographics, HIV and medical histories were recorded. Males underwent baseline semen analysis and seminal HIV viral load testing. Females had full fertility screens. Both partners were screened for sexually transmitted infections. All couples used timed ovulatory intercourse (TOI). Tenofovir±emtricitabine was taken by the female at protocol designated times before±after TOI. Thirty-two male positive/female negative couples used the services. Thirteen couples have used PrEP-C (median age of male 41 years (range 32-56), female 31 (28-43); median CD4 533 (236-1194); all male plasma and seminal HIV viral loads were undetectable). Eleven pregnancies in 10 couples have resulted in 7 live births, 1 ongoing pregnancy and 4 miscarriages (5/40, 6/40, 10/40 and 1 twin 17/40) after a median of 2.5 attempts (range 1-5). PrEP-C was well tolerated with no discontinuations and no HIV transmissions. These data suggest that PrEP-C is a safe and effective option for serodiscordant couples wishing to conceive; a standardised protocol has been developed; data collection via a central database is under way.

Spontaneous clearance and treatment of acute hepatitis C infection in HIV-positive men with 48 weeks of interferon-alpha and ribavirin.

Acute hepatitis C infection in the context of HIV is an emerging problem in men who have sex with men (MSM). We conducted a retrospective cohort study of MSM diagnosed with and treated for acute hepatitis C infection over 10 years. Genotype 1 was the commonest type representing 69% of cases; the spontaneous clearance rate was 20%. The overall sustained virological response (SVR) rate on an intention-to-treat basis was 83%; SVR and was 92% for those completing 48 weeks of treatment. The presence of detectable RNA at week 12 had a 100% negative predictive value for SVR. This is the largest single cohort treated with 48 weeks of interferon and ribavirin and the treatment SVR is one of the highest reported. We propose that a 48-week treatment regimen may be superior to shorter (24-week) regimens though we acknowledge the need for a randomized controlled trial.

British HIV Association guidelines for the management of HIV infection in pregnant women 2012.

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of human immunodeficiency virus (HIV)-positive pregnant women in the UK. The scope includes guidance on the use of antiretroviral therapy (ART) both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration,such as coinfection with other agents. The guidelines are aimed at clinical professionals directly involved with, and responsible for, the care of pregnant women with HIV infection.

Simultaneous measurement of urinary albumin and total protein may facilitate decision-making in HIV-infected patients with proteinuria.

OBJECTIVE: We recently showed that a urine albumin/total protein ratio (uAPR) <0.4 identifies tubular pathology in proteinuric patients. In tubular disorders, proteinuria is usually of low molecular weight and contains relatively little albumin. We tested the hypothesis that uAPR is useful in identifying tubular pathology related to antiretroviral use in HIV-infected patients. METHODS: We retrospectively identified urine protein/creatinine ratios (uPCRs) in HIV-infected patients. A subset of samples had uPCR and urine albumin/creatinie ratio (uACR) measured simultaneously. We classified proteinuric patients (uPCR >30 mg/mmol) into two groups: those with predominantly 'tubular' proteinuria (TP) (uAPR <0.4) and those with predominantly 'glomerular' proteinuria (GP) (uAPR ≥ 0.4). RESULTS: A total of 618 of 5244 samples from 1378 patients had uPCR ≥ 30 mg/mmol. uAPRs were available in 144 patients: 46 patients (32%) had TP and 21 (15%) GP; the remainder had uPCR <30 mg/mmol. The TP group had a higher fractional excretion of phosphate compared with the GP group (mean 27% vs. 16%, respectively; P<0.01). Patients with TP were more likely to be on tenofovir and/or a boosted protease inhibitor compared with those with GP. In 18 patients with heavy proteinuria (uPCR >100 mg/mmol), a renal assessment was made; eight had a kidney biopsy. In all cases, the uAPR results correlated with the nephrological diagnosis. CONCLUSIONS: In HIV-infected patients, measuring uAPR may help to identify patients in whom a renal biopsy is indicated, and those in whom tubular dysfunction might be an important cause of proteinuria and which may be related to antiretroviral toxicity. We suggest that this would be useful as a routine screening procedure in patients with proteinuria.

Reduced glomerular filtration rate but sustained virologic response in HIV/hepatitis B co-infected individuals on long-term tenofovir.

Reports have described a decrease in glomerular filtration rate (eGFR) associated with tenofovir disoproxil fumarate (TDF) use in HIV positive individuals. However, no study has examined renal function over a prolonged period in HIV/hepatitis B virus (HBV) co-infected patients. We assessed the long-term durability and toxicity of TDF in a cohort of 39 e antigen (eAg) positive co-infected patients commenced on TDF 245 mg daily either in addition to or as part of standard antiretroviral therapy. Immunological and virological parameters were followed to 260 weeks, with the median follow-up period being 251 weeks (range 69-290 weeks). eGFR was calculated using the Modification in Diet in Renal Disease equation. On treatment at 260 weeks, 88% (14/16) had HIV viral load <50 copies/mL, median CD4 count rose from 318 to 532 cells/mm(3), median alanine aminotransferase (ALT) fell from 61 IU/L to 42 IU/L, with 35% (7/20) having a normal ALT, median HBV DNA fell from 69 x 10(6) copies/mL to 500 copies/mL, with 75% (12/16) having an undetectable HBV DNA level and 55% (6/11) becoming eAg negative. Of those with detectable HBV DNA, none had TDF resistance mutations. The eGFR declined by 22.19 mL/min/1.73 mm(2) from baseline (P = 0.023) over this period, which was unaffected by protease inhibitor use, baseline CD4 count, ALT or HBV DNA level. Three patients discontinued TDF therapy due to renal dysfunction. In conclusion, TDF has sustained efficacy but is associated with a significant decline in eGFR. Further larger studies are required to clarify this observation.

The prevalence of reduced zidovudine susceptibility in zidovudine-naive, antiretroviral-experienced HIV-1-infected patients.

OBJECTIVES: There is increasing in vitro and in vivo evidence that reduced zidovudine (ZDV) susceptibility is generated by the selective pressure conferred by other nucleoside reverse transcriptase inhibitors (NRTIs). However, the degree to which this occurs in clinical practice remains unclear. We assessed phenotypic and genotypic resistance in ZDV-naive patients with virological failure on stavudine (d4T)-containing regimens, with particular reference to potential cross-resistance between d4T and ZDV. METHODS: Patients were identified from a clinical database. Treatment history was confirmed by case note evaluation and discussion with patients. Genotypic and phenotypic analyses were undertaken by Virco (Virco BVBA, Mechelen, Belgium). RESULTS: Sixty-seven drug-experienced, ZDV-naive patients who underwent a resistance test while failing a d4T-containing regimen were identified. Of these patients, 23% had received three or more NRTIs and 42% at least one non-nucleoside reverse transcriptase (RT) inhibitor; 22% had viruses with reduced d4T susceptibility (>1.8-fold resistance), and 25% had viruses with reduced ZDV susceptibility (>4-fold). The most frequently observed RT mutations were identified. A significant correlation was found between susceptibility to d4T and susceptibility to ZDV (r=0.36; P=0.003), and also between virtual resistance to d4T and that to ZDV (r=0.38; P=0.002). CONCLUSIONS: A significant minority of d4T-treated, ZDV-naive patients were found to have viruses with reduced ZDV susceptibility, with a variable association with classical ZDV resistance mutations. These data suggest that cross-resistance between d4T and ZDV may involve novel constellations of mutations. Correlations between d4T and ZDV susceptibilities and resistances further support cross-resistance between NRTIs.

Can targeted HIV testing campaigns alter health-seeking behaviour?

This paper describes the evaluation of 'gimme 5 minutes' a multimedia HIV testing campaign aimed at gay and bisexual men in London particularly targeting those of Black and South European Origin and those under the age of 25 years old using peer images. The text linked a summary of the key issues of a pre-test discussion with detailed information on how to access testing at a specified testing centre (campaign clinic). The number and demographics of men who reported sex with men (MSM) testing at the campaign clinic were monitored and compared with those testing at two other central London clinics. There was a 4.5-fold rise (p < 0.001) in MSM testing at the campaign clinic. Increases were proportionately greater in the sub-populations targeted with peer images: South European origin, 14-fold rise (p < 0.001), Black origin, 6.5-fold rise (p = 0.003), and MSM under 25 years old, 9.5-fold rise (p < 0.001). There were no significant changes in the number of MSM testing for HIV at the two other central London clinics studied. The results suggest that including detailed information about accessing testing services may be a vital ingredient in the success of media campaigns focusing on HIV testing.