Prevalence of HIV indicator conditions in late presenting patients with HIV: a missed opportunity for diagnosis?

AIM: To evaluate prior prevalence of HIV indicator conditions in late-presenters with HIV infection. DESIGN: Retrospective cohort study between 2000 and 2014 in a healthcare network in Melbourne, Australia comparing patients presenting with late diagnosis of HIV infection (CD4 < 350 cells/ml) to those patients who had a CD greater than or equal to 350 cells/ml at presentation. METHOD: The European AIDS Clinical Society guidelines on HIV indicator guided testing were used to assess for any indicator conditions in their prior medical history which may have represented a missed opportunity for earlier diagnosis. Main outcome measures: Descriptive statistics and prevalence of HIV indicator conditions. RESULTS: Of 436 patients with HIV infection, 82 were late presenters. Late presenters were more commonly male (83% vs. 75%, P = 0.11), older (mean age 45 vs. 39 years), born overseas (61% vs. 58%, P = 0.68) and report heterosexual transmission as their exposure risk (51% vs. 31%, P < 0.001). Of 80 patients with late presentation of HIV infection, 54 (55%) had at least one, 29 (36%) at least 2, 12 (15%) at least 3 and 5 (6%) had 4 or more previous HIV indicator conditions which would have triggered HIV testing according to guidelines. The most common indicator conditions were: unexplained loss of weight (31%), herpes zoster (10%), thrombocytopenia or leukopenia (10%), oral or oesophageal candidiasis (10%) and community acquired pneumonia (9%). Twenty patients (25%) had HIV indicator conditions diagnosed at least 12 months before the eventual diagnosis of HIV infection. DISCUSSION/ CONCLUSION: Patients diagnosed with late-presenting HIV often had an HIV indicator condition prior to presentation, presenting a missed opportunity for earlier diagnosis.

HIV in practice: current approaches and challenges in the diagnosis, treatment and management of HIV infection in Australia.

As treatment improves, people living with HIV (PLWHIV) can now expect to live longer, which means that the foci of HIV-related care for them and their medical practitioners continue to change. With an increasingly older cohort of patients with HIV infection, practitioners' key considerations are shifting from issues of acute treatment and patient survival to multiple comorbidities, toxicities associated with chronic therapy, and ongoing health maintenance. Within this context, this paper explores the current standard of practice for the management of HIV infection in Australia. We surveyed 56 Australian practitioners currently involved in managing HIV infection: 'HIV section 100' (HIV therapy-prescribing) general practitioners (s100 GPs; n = 26), sexual health physicians (SHPs; n = 24) and hospital-based physicians (HBPs; n = 6). Survey results for practice approaches and challenges were broadly consistent across the three practitioner specialties, apart from a few key areas. s100 GPs reported less prophylaxis use among patients whom they deemed at risk of HIV infection in comparison with SHPs, which may reflect differences in patient populations. Further, a higher proportion of s100 GPs nominated older HIV treatment regimens as their preferred therapy choices compared with the other specialties. In contrast with SHPs, s100 GPs were less likely to switch HIV therapies to simplify the treatment protocol, and to immediately initiate treatment upon patient request in those newly diagnosed with HIV infection. Considerably lower levels of satisfaction with current HIV practice guidelines were also reported by s100 GPs. It appears that greater support for s100 GPs may be needed to address these identified challenges and enhance approaches to HIV practice. Across all specialties, increasing access to mental health services for patients with HIV infection was reported as a key management issue. A renewed focus on providing improved mental health and wellbeing supports is recommended, particularly in the face of an ageing HIV-infected population.

New HIV diagnosis after occupational exposure screening: the importance of reporting needlestick injuries.

We describe three new diagnosis of HIV infection as a direct result of testing following occupational exposures (NSIs) in a low-prevalence setting. In each case the finding was unexpected. Our series provides a reminder of the importance of prompt reporting of NSIs by healthcare workers, access to rapid HIV testing and post-exposure prophylaxis with antiretrovirals to prevent transmission.

Rat bite fever as a presenting illness in a patient with AIDS.

The etiology of culture-negative septic arthritis is poorly characterised in persons infected with human immunodeficiency virus (HIV). New molecular methods may assist in the investigation of culture-negative infections of sterile sites, including septic arthritis. We describe the first case of septic arthritis due to the cause of rat bite fever (RBF), Streptobacillus moniliformis, confirmed by 16S rRNA sequence analysis, in a patient with newly diagnosed HIV infection.

Southeast Asian ovalocytosis is associated with increased expression of Duffy antigen receptor for chemokines (DARC).

The Duffy antigen receptor for chemokines (DARC or Fy glycoprotein) carries antigens that are important in blood transfusion and is the main receptor used by Plasmodium vivax to invade reticulocytes. Southeast Asian ovalocytosis (SAO) results from an alteration in RBC membrane protein band 3 and is thought to mitigate susceptibility to falciparum malaria. Expression of some RBC antigens is suppressed by SAO, and we hypothesized that SAO may also reduce Fy expression, potentiallyleading to reduced susceptibility to vivax malaria. Blood samples were collected from individuals living in the Madang Province of Papua New Guinea. Samples were assayed using a flow cytometry assay for expression of Fy on the surface of RBC and reticulocytes by measuring the attachment of a phycoerythrin-labeled Fy6 antibody. Reticulocytes were detected using thiazole orange. The presence of the SAO mutation was confirmed by PCR. There was a small (approximately 10%) but statistically significant (p=0.049, Mann-Whitney U test) increase in Fy expression on SAO RBC compared with RBC from individuals without this polymorphism: mean Fy expression (mean fluorescence intensity [MFI]) was 10.12 +/- 1.22 for SAO heterozygotes versus an MFI of 8.95 +/- 1.1 for individuals without SAO. For reticulocytes the MFI values were 27.61 +/- 19.12 for SAO heterozygotes and 16.47 +/- 3.81 for controls. SAO is associated with increased and not decreased Fy6 expression so that susceptibility to P. vivax infection is unlikely to be affected.

Duffy antigen expression on reticulocytes does not alter following blood loss in an autologous donation model.

BACKGROUND: The Duffy blood group (Fy) antigen functions as the receptor whereby the malarial parasite Plasmodium vivax invades reticulocytes. In this study, we evaluated an autologous blood donation model to measure Fy expression during the anticipated response to blood loss. AIMS: This study aims to examine Fy expression following anticipated reticulocytosis in response to blood loss from autologous whole blood donation. METHOD: Subjects were healthy blood donors presenting for planned collection of two or three autologous units. Whole blood (450 ml +/- 10%) was collected and processed. Blood samples for Fy testing were obtained from the donations. These were assayed by flow cytometry by measuring binding of a phycoerythrin-labelled anti-Fy6 antibody and compared against reticulocyte numbers. Reticulocyte numbers were measured using thiazole orange. Results were compared from baseline (first donation) with samples at second and, if available, third, donations. Phenotyping for Fy a and b antigens was performed. RESULTS: Reticulocytes increased by a mean of 37% over baseline [0.93% (range 0.31-1.93) to 1.23% (0.32-3.51%)] following donation of two (n = 32) or three (n = 9) autologous whole blood units. Absolute reticulocyte count remained low. Mean and median Fy expression on mature red blood cells and reticulocytes did not change from baseline levels despite individual variation. No apparent relationship to serologically determined Fy a and/or b antigen status was present. CONCLUSION: Baseline expression of Fy antigen on mature red blood cells and reticulocytes is quite variable between individuals, but appears not to be greatly affected by mild to moderate reticulocytosis following blood loss in an autologous blood donation model.

Prevalence of and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993-2006.

OBJECTIVES: The aim of the study was to describe the prevalence of and risk factors for HIV-associated sensory neuropathy (HIV-SN) in 2006 [the era of stavudine, didanosine and zalcitabine (dNRTI)-sparing highly active antiretroviral therapy (HAART)] and to compare our findings with data obtained in the same clinic in 1993 (pre-HAART) and 2001 (frequent use of dNRTI-containing HAART). METHODS: This was a cross-sectional comparative study using convenience sampling. HIV-positive adults attending a tertiary referral clinic over a 2-week period were screened for HIV-SN using the AIDS Clinical Trials Group screening tool. HIV-SN was defined as present if the patient had both neuropathic symptoms and abnormal signs. Demographic, clinical, laboratory and treatment data were considered as possible risk factors for HIV-SN, and results were compared with data obtained in the same clinic in 1993 and 2001. RESULTS: One hundred patients were screened. The prevalence of HIV-SN was 42%, which was unchanged since 2001 (44%) despite a significant reduction in the use of dNRTIs. HIV-SN remained much more common than in 1993 (42% vs 13%; P<0.0001). The only independent associations with HIV-SN in 2006 were increasing patient age and a history of exposure to either stavudine or indinavir. This compares with 1993 when neuropathy was increased in those with Mycobacterium avium complex infection, and 2001 when patient age and use of stavudine and didanosine were the independent associations with HIV-SN in this clinic. CONCLUSIONS: HIV-SN remained common among ambulatory patients in 2006 (42% prevalence) despite a significant reduction in the use of dNRTIs. In addition to patient age and stavudine exposure, indinavir use may be a risk factor for HIV-SN.

Rat-bite fever septic arthritis: illustrative case and literature review.

Rat-bite fever is a rare zoonotic infection caused by Streptobacillus moniliformis or Spirillum minus, which is characterised by fever, rash and arthritis. The arthritis has previously been described as non-suppurative and isolation of the organism from synovial fluid as very uncommon. This article reports a case of septic arthritis diagnosed as rat-bite fever when the organism was cultured from synovial fluid and reviews another 15 cases of S. moniliformis septic arthritis reported in the worldwide literature since 1985. Articles were included in this review if S. moniliformis was cultured from synovial fluid. Of the published cases, 88% presented with polyarthritis, affecting small and large joints although two had monoarticular hip sepsis. Fever was present in 88%, rash in 25% and 56% had extra-articular features. Synovial fluid analysis revealed high cell counts in all cases (mean 51,000 x 10(9)/l) with a predominance of polymorphonuclear leucocytes, and organisms were found on Gram stain in only 50%. Penicillin was used for treatment in 56% of cases and surgery was required in 30%. All patients recovered. Rat-bite fever arthritis can be suppurative and attempts should be made to isolate the organism from synovial fluid. The diagnosis should be considered when there is arthritis and a high synovial fluid cell count but no apparent organism, especially when the patient has had contact with rats.

Expression of Duffy antigen receptor for chemokines during reticulocyte maturation: using a CD71 flow cytometric technique to identify reticulocytes.

Flow cytometric methods commonly used to identify reticulocytes are of limited usefulness in malarious areas, since RNA staining also detects plasmodia. An important antigen expressed on reticulocytes is Duffy antigen receptor for chemokines (DARC, also known as Fy), the receptor for Plasmodium vivax. An early marker for reticulocytes is CD71 (transferrin receptor). We have been interested in CD71 as an alternative marker for reticulocytes in the context of Fy expression. Flow cytometry was used to determine the expression of Fy on CD71-positive and -negative reticulocytes and to correlate serology and genotype. A reduction of 13 percent was seen in Fy6 expression between CD71-positive reticulocytes and RNA-positive reticulocytes. CD71 disappears early during reticulocyte maturation, while Fy6 expression is relatively preserved. CD71 is an alternative to staining for RNA for reticulocyte assays relating to Fy6 expression.

Chlamydia pneumoniae in HIV-infected patients and controls assessed by a novel whole blood interferon-gamma assay, serology and PCR.

Chlamydia pneumoniae seropositivity is associated with cardiovascular disease and HIV infection. Cell-mediated immune responses are important for control of C. pneumoniae, and such responses may be impaired in HIV-infected patients. An assay for detection of interferon (IFN)-gamma in whole blood stimulated with C. pneumoniae antigen was developed and studied in HIV-infected patients and uninfected controls. Among 34 HIV-infected patients, none had an IFN-gamma response to C. pneumoniae antigen, compared with five of 32 healthy controls (p < 0.001). Fewer HIV-infected individuals elicited a serum IgG response when tested with a commercial enzyme immunoassay (p 0.009), but this was not so for serum IgA (p 0.12). Additionally, the IFN-gamma and antibody assays showed a trend towards a bivariate response in normal controls. This indicates that cellular and antibody responses against C. pneumoniae may be mutually exclusive, with potential implications for the role of this organism in the genesis of cardiovascular disease in both immunocompetent and HIV-infected populations.

HIV nephropathy and the Duffy antigen/receptor for Chemokines in African Americans.

BACKGROUND AND OBJECTIVES: HIV nephropathy (HIVAN) is markedly racially biased in its distribution, occurring in about 10% of HIV infected African Americans according to some studies. Based upon previous laboratory and epidemiological studies, the Duffy promoter polymorphism, which occurs almost exclusively in individuals of African descent, has been postulated to be the predisposing factor. We aimed to explore that relationship by directly genotyping individuals with HIV nephropathy to determine the proportion homozygous for this mutation to test the hypothesis it was responsible for the genetic component of this disease. We anticipated that if the polymorphism was associated with HIV nephropathy all individuals would be homozygous for this mutation. METHOD: Individuals with HIVAN proven on biopsy were identified from previous studies and a pre-existing clinical database. This diagnosis was confirmed by an experienced pathologist examining the biopsies in a blinded fashion. PCR and RFLP strategies were used on the biopsy samples to genotype for the Duffy promoter polymorphism. The cases were compared to a control population of HIV seronegative African Americans. RESULTS: Twenty African American individuals with HIV nephropathy were successfully genotyped. Only nine were homozygous for the promoter mutation. Nine were heterozygous and two homozygous wild type. Furthermore, the frequency of the polymorphism did not differ from the background rate in the African American population (OR = 0.788 95% confidence intervals 0.378-1.64). CONCLUSION: The Duffy promoter polymorphism was not disproportionately represented in persons with HIVAN calling into question any significant role in the pathogenesis of HIVAN.

Changing spectrum of mortality due to human immunodeficiency virus: analysis of 260 deaths during 1995--1999.

We analyzed the deaths in an outpatient human immunodeficiency virus (HIV) care clinic at University Hospitals in Cleveland from January 1995 through December 1999. The number of annual deaths decreased progressively, from 112 in 1995 to 32 in 1999. The median final CD4(+) cell count before death increased progressively from 10 cells/microL in 1995 to 90 cells/microL in 1999 (P<.01); 20%--25% of patients who died from 1997 through 1999 had plasma HIV RNA levels below detection limits. From 1995 through 1998, deaths due to infection, to end-stage acquired immune deficiency syndrome, and to malignancies decreased, whereas the proportion of deaths due to end-organ failures and of uncertain relationship to HIV infection increased. The spectrum of mortality in HIV disease has changed recently; although opportunistic infections cause death less frequently, deaths are occurring in people who have control of HIV replication and with some preservation of immune function. These observations underscore the need to monitor the etiologies of HIV-associated mortality and to better our understanding of the relationships among immune defenses, treatment-related toxicities, and end-organ failure in patients with HIV disease.

Differential expression of the duffy antigen receptor for chemokines according to RBC age and FY genotype.

BACKGROUND: The Duffy (Fy) blood group (also known as Duffy antigen receptor for chemokines, or DARC) may be involved in regulation of the level of circulating proinflammatory chemokines, and it is an obligatory receptor on RBCs for the human malaria parasite Plasmodium vivax. STUDY DESIGN AND METHODS: Because quantification of Fy expression by using RBCs of various ages will not detect acute changes associated with inflammatory states, and because P. vivax exclusively invades reticulocytes, a flow cytometric method was developed to measure the level of surface expression of Fy. Reticulocytes and mature RBCs from persons with different genotypes (GATA-1 T-->C promoter mutation at nt -46; FY*A and FY*B in the ORF) were used. RESULTS: Expression of the Fy6 epitope, which is required for P. vivax invasion, was 49 +/- 19 percent higher on reticulocytes than on mature RBCs, regardless of donor genotype (p<0.0001). Fy6 levels were approximately 50 percent lower in persons who were heterozygous for the GATA-1 promoter mutation and were significantly lower on reticulocytes and mature RBCs of the FY*B/FY*B genotype than on those of the FY*A/FY*A or FY*A/FY*B genotype. CONCLUSION: Fy has greater expression on reticulocytes than on mature RBCs in flow cytometry. This method may be useful in further studies of this antigen, such as characterization of reticulocytes and RBC phenotypes across populations, in response to chemokine regulation, and in the context of susceptibility to P. vivax and other parasites.