Time to initiation of antiretroviral therapy in HIV-infected patients diagnosed with an opportunistic disease: a cohort study.

OBJECTIVES: The aim of the study was to identify factors associated with the time between opportunistic disease (OD) diagnosis and antiretroviral therapy (ART) initiation in HIV-infected patients presenting for care with an OD, and to evaluate the outcomes associated with any delay. METHODS: A multicentre cohort study was undertaken in London, Paris and Lille/Tourcoing. The medical records of patients diagnosed from 2002 to 2012 were reviewed. RESULTS: A total of 437 patients were enrolled in the study: 70% were male, the median age was 40 years, 42% were from sub-Saharan Africa, 68% were heterosexual, the median CD4 count was 40 cells/µL, and the most common ODs were Pneumocystis pneumonia (37%), tuberculosis (24%), toxoplasmosis (12%) and Kaposi's sarcoma (11%). Of these patients, 400 (92%) started ART within 24 weeks after HIV diagnosis, with a median time from OD diagnosis to ART initiation of 30 [interquartile range (IQR) 16-58] days. Patients diagnosed between 2009 and 2012 had a shorter time to ART initiation than those diagnosed in earlier years [hazard ratio (HR) 2.07; 95% confidence interval (CI) 1.58-2.72]. Factors associated with a longer time to ART initiation were a CD4 count ≥ 200 cells/µL (HR 0.30; 95% CI 0.20-0.44), tuberculosis (HR 0.40; 95% CI 0.30-0.55) and diagnosis in London (HR 0.62; 95% CI 0.48-0.80). Patients initiating 'deferred' ART (by ≥ 30 days) exhibited no difference in disease progression or immunovirological response compared with patients who had shorter times to ART initiation. Patients in the 'deferred' group were less likely to have ART modifications (HR 0.69; 95% CI 0.48-1.00) and had shorter in-patient stays (mean 14.2 days shorter; 95% CI 8.9-19.5 days) than patients in the group whose ART was not deferred. CONCLUSIONS: The time between OD diagnosis and ART initiation remains heterogeneous and relatively long, particularly in individuals with a high CD4 count or tuberculosis or those diagnosed in London. Deferring ART was associated with fewer ART modifications and shorter in-patient stays.

Discordant responses on starting highly active antiretroviral therapy: suboptimal CD4 increases despite early viral suppression in the UK Collaborative HIV Cohort (UK CHIC) Study.

OBJECTIVES: Patients starting highly active antiretroviral therapy (HAART) may have a suboptimal CD4 increase despite rapid virological suppression. The frequency and the significance for patient care of this discordant response are uncertain. This study was designed to determine the incidence of a discordant response at two time-points, soon after 6 months and at 12 months, and to determine the relationship with clinical outcomes. METHODS: Data obtained in the UK Collaborative HIV Cohort Study were analysed. A total of 2584 treatment-naïve patients starting HAART with HIV viral load (VL) > 1000 HIV-1 RNA copies/mL at baseline and < 50 copies/mL within 6 months were included in the analysis. Patients were classified at either 6-10 (midpoint 8) months or 10-14 (midpoint 12) months as having a discordant (CD4 count increase < 100 cells/microL from baseline) or concordant response (CD4 count increase >or= 100 cells/microL). RESULTS: Discordant responses occurred in 32.1% of patients at 8 months and in 24.2% at 12 months; 35% of those discordant at 8 months were concordant at 12 months. A discordant response was associated with older age, lower baseline VL, and (at 12 months) higher baseline CD4 cell count. In a multivariate analysis it was associated with an increased risk of death, more strongly at 12 months [incidence rate ratio (IRR) 3.35, 95% confidence interval (CI) 1.73-6.47, P < 0.001] than at 8 months (IRR 2.08, 95% CI 1.19-3.64, P = 0.010), but not with new AIDS events. CONCLUSIONS: Discordant responders have a worse outcome, but assessment at 12 months may be preferred, given the number of 'slow' responders. Management strategies to improve outcomes for discordant responders need to be investigated.

A multicentre, randomised, double-blind, placebo controlled study of cryotherapy versus cryotherapy and podophyllotoxin cream as treatment for external anogenital warts.

OBJECTIVES: To compare the efficacy and safety of combination therapy with cryotherapy and podophyllotoxin 0.15% cream versus cryotherapy alone in the treatment of anogenital warts. METHODS: A randomised, double-blind, multicentre controlled trial. Patients received podophyllotoxin cream or placebo twice daily for 3 days/week for up to 4 weeks, with weekly cryotherapy continued to week 12 if required. Further treatment from week 12 to 24 was discretionary. Patients were stratified by sex and history of warts. HIV positivity, warts treated in the past 4 months, or warts with a combined area of less than 10 mm(2) were exclusion criteria. Primary endpoints were clearance at weeks 4 and 12. RESULTS: 70 patients per group were randomly assigned and started treatment; 101 first-episode warts, 91 male. No treatment-related serious adverse events were reported. Follow-up at week 12 was 85%. By intention-to-treat analysis, clearances at 4 and 12 weeks were higher in the combination group (60.0% and 60.0%, respectively) than with cryotherapy alone (45.7%, 45.7%) although not statistically significant (RR 1.31, 95% CI 0.95 to 1.81). By week 24 there was no difference between the groups (68.6% and 64.3%, respectively; RR 1.07, CI 0.84 to 1.35). At week 4, wart clearance was higher in men (p = 0.001) and those with a past history of warts (p = 0.009), but these differences were not detected at week 12. There was some evidence for a higher relapse rate in the group receiving cryotherapy alone. CONCLUSIONS: Initial combination therapy with podophyllotoxin/cryotherapy was well tolerated and may have resulted in earlier clearance in some patients, compared with cryotherapy alone; however, overall differences in clearance rates were not statistically significant.

Rectal gonorrhoea in men -- is microscopy still a useful tool?

Rectal gonorrhoea (GC) in men may cause anal discharge or proctitis, but these symptoms have been shown to correlate poorly with rectal infection. Culture of Neisseria gonorrhoeae from an exposed site offers a readily available, sensitive and cheap diagnostic test, and is currently the gold standard for diagnosis; however, these results can take a few days and therefore do not offer an instant diagnosis. Gram staining of rectal smears for N. gonorrhoeae has a low sensitivity but a high specificity when performed by experienced personnel. We audited whether rectal microscopy increased the number of patients diagnosed and treated for rectal GC at initial presentation at one inner London genitourinary clinic over a 12-month period. One hundred and thirty-six episodes of rectal GC were identified in 132 men. In all, 134/136 had rectal microscopy of whom, 47/134 (35%) were smear-positive for GC. Of the 136 cases, 90 received antibiotics for GC at their first presentation. Twenty-four of 90 (27%) would not have been treated until culture results were available, if rectal microscopy had not been performed. These results suggest that rectal microscopy remains an important tool and increases the proportion of men treated for GC at their first attendance.

No effect of zidovudine on hepatitis B virus replication in homosexual men with symptomatic HIV-1 infection.

Zidovudine triphosphate inhibits the hepatitis B virus (HBV) DNA polymerase (DNAp) in vitro. Serial measurements of serum HBV DNAp activity and HBV DNA were made in 14 consecutive male homosexual patients starting zidovudine for symptomatic HIV-1 infection. Median duration of treatment was 15 weeks (range 2-72). In the 13 patients with detectable DNAp/DNA pre-treatment, no significant change in either measure of viral replication was observed during the first 16 weeks of treatment compared with the 13 weeks prior to treatment. The lack of response may be due to the opposing effect of immunosuppression, or to a failure of in vivo activity.

Hepatitis B virus reactivation or reinfection associated with HIV-1 infection.

Following acute hepatitis B virus (HBV) infection, most individuals develop antibodies to HBV surface (anti-HBs) and core antigen (anti-HBc). Prevalence studies have shown that 10-18% develop anti-HBc in the absence of detectable anti-HBs. We report four such cases, all with persistence of serum anti-HBc, who had evidence of a second period of active HBV replication as demonstrated by the reappearance of serum hepatitis B surface antigen (HBsAg). In one patient, an HBsAg subtype difference indicated that the second period of HBsAg-positivity was due to a reinfection. In the other cases, reactivation may also explain the findings. All cases were anti-HIV-1 seropositive at the time of reappearance of HBsAg. There is experimental evidence that anti-HBc has a protective effect against HBV infection; however, this may require intact cell-mediated immunity to be effective. HIV-1 infection may render such patients susceptible to reinfection. Alternatively, some patients with anti-HBc, but without detectable anti-HBs may have latent HBV infection. Immunosuppression associated with HIV-1 infection may allow reactivation.

Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection.

OBJECTIVES: Hepatitis B virus (HBV) and HIV infections share risk-factors; therefore coinfection is common. Interactions have been reported but controlled studies have been limited. Our objective was to study the effect of HIV infection on the natural history of chronic HBV infection and the reverse effect of the HBV carrier state on HIV infection. DESIGN: Prospective observational cohort study. SETTING: Open-access outpatient HIV/genitourinary medicine clinic at a Central London hospital. PATIENTS: Total of 152 untreated homosexual male HBV carriers and 212 HBV surface antigen-negative controls (41.4 and 70.3% HIV-seropositive, respectively). OUTCOME MEASURES: The rate of loss of serum HBV e antigen (HBeAg) and its reappearance in HIV-infected and HIV-uninfected HBV carriers; serum HBV DNA levels measured by dot-blot hybridization assay), HBV DNA polymerase activity and liver transaminase activities, the progression of HIV infection to symptomatic disease or AIDS in HIV-infected compared with HBV-HIV coinfected patients. RESULTS: In HIV-infected HBV carriers, serum HBV DNA polymerase activity was higher, alanine aminotransferase was lower and loss of serum HBeAg (mean follow-up, 2.8 years) occurred at a lower rate when compared with HIV-uninfected HBV carriers (estimated relative hazard, 0.39; 95% confidence interval, 0.161-0.942) Concomitant chronic HBV infection had no detectable effect on the rate of progression of HIV disease after correction for lead-time bias. CONCLUSION: This study strengthens the evidence for a significant effect of HIV infection on the natural history of chronic HBV infection, which by prolonging the period of infectivity could have an important impact on the epidemiology of HBV infection in regions, or patient groups, with high HIV seroprevalence. There was no evidence of an important effect of HBV carriage on HIV disease progression.

HIV infection alters the production of both type 1 and 2 cytokines but does not induce a polarized type 1 or 2 state.

OBJECTIVE: To test the T-helper (TH)1/TH2 cytokine paradigm in HIV infection. DESIGN AND METHODS: Cytokine profiles in two separate studies of HIV patients and controls are presented: (i) a longitudinal study of HIV patients with CD4 counts > 500 x 10(6)/l tested at three timepoints compared with controls; (ii) a blinded cross-sectional study of controls and patients with high (> 500 x 10(6)/l) and low (< 500 x 10(6)/l) CD4 counts. Peripheral blood mononuclear cells (PBMC) from patients and controls were tested for the production of two type 1 [interleukin (IL)-2, interferon (IFN)-gamma] and two type 2 (IL-4, IL-10) cytokines by enzyme-linked immunosorbent assay. Both spontaneous and mitogen-induced cytokine production was measured. RESULTS: HIV infection was noted to have the following effects on cytokine production: (i) it led to the in vivo activation of type 2 cytokines in a small group of individuals with high CD4 numbers characterized by the spontaneous release of IL-4 and IL-10. Longitudinal data showed high spontaneous IL-4 and IL-10 to be a consistent feature of the patient group (at each timepoint some patients were high producers) but to be variable in a given individual; (ii) HIV infection impaired the ability of PBMC to respond to stimuli (selected for their ability to optimally induce each cytokine) in terms of IL-2, IL-4 and IL-10 production in patients with both high and low CD4 cell counts; and (iii) conversely, HIV infection led to an overproduction of IFN-gamma in patients with high CD4 counts; patients with low CD4 produced normal levels of IFN-gamma. CONCLUSIONS: Our observations did not suggest polarization of the type 1/type 2 cytokine profile in HIV patients. Instead, the data suggested more complex changes to type 1/type 2 cytokine patterns in HIV infection than originally proposed by the TH1/TH2 dichotomy.

A randomized, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIV-infected patients. Imiquimod Study Group.

OBJECTIVE: To assess the safety of imiquimod, an immune response modifier, in the topical treatment of external anogenital warts in HIV-infected patients. SETTING: Clinical sites in the United Kingdom (eight) and the United States (five). DESIGN: A prospective, randomized, double-blind, vehicle-controlled study of imiquimod 5% cream or vehicle applied for 8+/-2 h three times per week for a maximum of 16 weeks in HIV-seropositive males (n = 97) and females (n = 3) aged 18 years or more with clinically diagnosed external anogenital warts, CD4 T lymphocyte count of > or = 100 x 10(6) cells/l and Karnofsky score > or = 70. MAIN OUTCOME MEASURES: Safety was assessed through the incidence and severity of local skin reactions and other adverse events, and through clinical laboratory tests. Wart clearance was documented by two-dimensional measurements of warts and by photography. RESULTS: Among the patients treated with imiquimod (n = 65) and vehicle (n = 35), the most common local skin reaction was erythema, (41.9 and 26.7%, respectively) and the incidence of patients reporting at least one adverse event was 69.2 and 65.7%, respectively. No clinically meaningful differences or changes in laboratory values were observed between treatment groups, nor were drug-related adverse effects observed in regard to HIV disease. While there was no significant difference between treatment groups in the number of patients who totally cleared their baseline warts (imiquimod 11% versus vehicle 6%, P = 0.488), more imiquimod-treated patients experienced a > or = 50% reduction in baseline wart area (38% versus 14%, P = 0.013). CONCLUSION: Most local skin reactions were mild and no adverse effects on HIV disease were observed. Topically applied imiquimod 5% cream reduced wart area and may have clinical utility in treating external anogenital warts in some HIV-infected patients.

Similarity of male and females of HDL2 and HDL3 cholesterol concentration in A caribbean rural community.

Fasting serum lipoprotein lipid concentrations were measured in 64 subjects aged 11-18 and 72 aged 33-54 years, who comprised 86% of long-term residents of these ages in a rural community in Trinidad. Total HDL, HDL2, and HDL3 cholesterol concentrations were similar in males and females after allowance for alcohol consumption. The results differ from other societies in which HDL2 concentration is lower in men than women, and are thought to provide further evidence for interaction between hormonal status and factors such as adiposity and triglyceride concentration with respect to HDL concentration.

HBV DNA levels and transmission of hepatitis B by health care workers.

BACKGROUND: Laboratory-based study funded by the Research and Development Division of the Department of Health to inform the decision making on guidelines for the conduct of exposure prone procedures (EPPs) by health care workers who are hepatitis B carriers. OBJECTIVES: Define the quantity and nature of hepatitis B virus (HBV) DNA in hepatitis carriers whose serum does not contain hepatitis B e antigen (HBeAg) and in surgeons previously cleared to conduct EPPs who have transmitted HBV to their patients. STUDY DESIGN: Cross-sectional survey using HBV DNA quantification, genotyping and sequencing comparing transmitting surgeons and asymptomatic carriers. RESULTS: HBV DNA could be detected and quantified in 64.5% (136 of 211) of carriers whose serum did not contain HBeAg with a median level 3.6 log(10) copies/ml (range of 5.7 log(10) copies). Pre-core mutation appeared not to affect the HBV DNA level, however, all surgeons carried codon 28 variants and transmitted these variants to their patients. The lowest HBV DNA level in a transmitting surgeon was 4 x 10(4) copies/ml. CONCLUSIONS: Pre-core mutations are common in carriers whose serum does not contain HBeAg and do not specifically identify carriers whose HBV DNA levels are high. It was possible to define a level of virus above which transmission of hepatitis B during conduct of EPPs could not be excluded.

Hepatitis B nucleotide sequence analysis: linking an outbreak of acute hepatitis B to contamination of a cryopreservation tank.

An epidemiological investigation indicated that six patients treated in a haematology unit who developed acute hepatitis B may have been infected as a result of contamination of a liquid nitrogen bone marrow storage tank. The clinical details are described elsewhere (Tedder et al., 1995); we describe the virological methods used to support the findings. HBV DNA was amplified from sera using a nested PCR with primers for the surface gene, and a region encompassing precore, the 3' end of X, and the 5' end of core. HBV DNA was also extracted from the frozen detritus in the liquid nitrogen storage tank. After equilibration, the aqueous material was filtered, co-precipitated with albumin and polyethylene glycol and the HBV DNA extracted by phenol-chloroform and ethanol precipitation. Direct nucleotide sequence analysis indicated that four patients were infected with HBsAg subtype adw viruses which carried novel amino acid substitutions at codons 145 and 146 of the X gene. HBV DNA extracted from the storage tank detritus contained identical sequences. The samples from two other patients, subtype ayw, did not contain the novel sequence changes in X and had other sequence differences. These findings linked conclusively the four patients as a cluster and the rescue of HBV-DNA sequences from the contaminated storage tank by the method described confirmed this as the common source of infection. Two other HBsAg-positive patients were excluded from the cluster by sequence analysis. Demonstration of infection by this route has implications for the safe storage of bone marrow and other related biological materials.

Suicide-substrate inactivation of beta-galactosidase by diazomethyl beta-D-galactopyranosyl ketone.

Diazomethyl beta-D-galactopyranosyl ketone (1) has been proven to be a mechanism-based, irreversible (suicide-substrate) inactivator of Aspergillus oryzae beta-D-galactosidase, but not an inactivator of E. coli lacZ beta-D-galactosidase. Compound 1 is stable in buffers of normal physiological pH. It is decomposed by H+, but not by nucleophiles. Inactivation of A. oryzae beta-D-galactopyranosyl ketone (2) nor diazomethyl alpha-D-galactopyranosyl ketone inactivated the enzyme and therefore inactivation is stereospecific, excess inhibitor could be separated from inactive enzyme without regain of activity and therefore it is bound irreversibly, and a second pulse of enzyme is inactivated at the same rate as enzyme inactivated to 95% activity by the first pulse. Diazomethyl beta-D-glucopyranosyl ketone (2) inhibited sweet almond beta-D-glucosidase.

Failure to deliver hepatitis B vaccine: confessions from a genitourinary medicine clinic.

OBJECTIVE: To audit hepatitis B immunisation of homosexual or bisexual men in a genitourinary medicine clinic. DESIGN: Retrospective case note review of all homosexual and bisexual men presenting to a genitourinary clinic as new patients during 12 months in 1988 and follow up review of notes to May 1990. SETTING: One department of genitourinary medicine, Middlesex Hospital. PATIENTS: 758 homosexual or bisexual men, of whom 207 started a course of hepatitis B vaccine in 1988. Case notes were unavailable for one patient. MAIN OUTCOME MEASURES: The proportion of patients screened for hepatitis B virus markers, the proportion of susceptible patients immunised, the proportion completing the vaccine course, and the proportion rendered immune. RESULTS: 25 men had been previously tested for hepatitis markers; of the 732 not previously tested, 440 (60.1%) were screened for hepatitis B markers. 207 (69%) of the 300 patients without hepatitis B serological markers started the vaccine course, and 141 (68%) completed it, with 75 (84%) of the 89 tested after immunisation being immune. An estimated 24% of susceptible new patients were rendered immune as a result of the immunisation policy. Patients who presented with a further episode of a sexually transmitted disease were more likely to have been screened (25% v 12%, p less than 0.0001) and immunised (31% v 18% p = 0.02); those known or found to be positive for HIV antibody were more likely to have been screened (23% v 14%, p = 0.047) but less likely to have been immunised (6% v 17%, p = 0.004). CONCLUSIONS: The major failure was that in not screening; failure to immunise patients found to be susceptible and failure of compliance with the vaccine course contributed. Non-response to the vaccine was of minor importance. Improvements in vaccine delivery are required. IMPLICATIONS: Other providers should be encouraged to review their performance.

Hepatitis C virus: evidence for sexual transmission.

OBJECTIVE: To determined the prevalence of hepatitis C virus infection and associated risk factors in patients attending a genitourinary medicine clinic, as evidence for sexual transmission. DESIGN: Seroprevalence estimated by reactivity in an enzyme immunoassay for antibodies to C100 protein with supplementary testing with a recombinant immunoblot assay and an assay for hepatitis C virus RNA. SETTING: Outpatient genitourinary medicine clinic in central London. PATIENTS: The panel of 1046 serum samples was from 1074 consecutive patients attending the clinic during November and December 1987 and having blood taken for routine testing for syphilis. Before samples were anonymised demographic and risk factor information was extracted from the clinic notes. Samples had already been tested for antibody to HIV-I and antibody to hepatitis B core antigen. MAIN RESULTS: Significantly more homosexual subjects than heterosexual subjects were positive for hepatitis C antibody determined by enzyme immunoassay alone (19/275 (6.9%) v 8/771 (1.0%), odds ratio 7.14, p less than 0.0001) and also when reactive serum samples were also tested by recombinant immunoblot assay (6/270) (2.2%) v 3/770 (0.4%), odds ratio 5.88, p less than 0.02). There were also significant associations in patients positive for hepatitis C antibody with positivity for antibodies to HIV and to hepatitis B core antigen, lifetime number of sexually transmitted diseases (homosexual men only), and age (all groups combined). Most patients whose serum samples contained specific antibodies to hepatitis C virus were viraemic. CONCLUSIONS: The study provides strong evidence for the sexual transmission of hepatitis C virus. Assays derived from other gene products are desirable to investigate the specificity and sensitivity of the enzyme immunoassay for C100 antibody as a marker of hepatitis C virus infection.

Routine detection and management of neurocognitive impairment in HIV-positive patients in a UK centre.

We estimated the burden of HIV-associated neurocognitive disorders (HAND) in a UK clinic. From a random sample, and referrals to specialist services over one year (neurology, clinical psychology, hospital admissions), we determined whether patients were diagnosed with HIV-associated dementia (HAD) and whether they reported symptoms suggesting neurocognitive impairment (NCI). In the first sample, 2/150 (prevalence 1.3%; 95% confidence interval [CI] 0.2-4.7%) had documented HAD. Eleven patients (7.3%; CI 3.7-12.7%) reported recent symptoms suggesting NCI; most of these individuals were diagnosed with a psychiatric or substance-use disorder. Among specialist referrals with symptoms suggesting NCI, 11 were diagnosed with HAD from a clinic population of 3129 individuals (annual incidence 0.4%; CI 0.2-0.6%). No patients with mildly symptomatic or asymptomatic HAND were identified in either sample, suggesting that such patients remain undetected in current clinical practice. Evidence-based screening for HAND in HIV clinics may be needed.