Search

New South Wales has the greatest burden of HIV in Australia, with 2012 and 2013 recording the highest rates of new diagnoses in 20 years. Concurrently, there has been significant changes in antiretroviral treatments and testing paradigms. We compiled a statewide resistance database to characterize changes in HIV-1 resistance mutations over time. Genotypic antiretroviral resistance testing (GART) was performed on request at three reference laboratories using commercial and in-house methods. In total, 7629 HIV-1 polymerase sequences obtained from GART from 2004 to 2013 were retrospectively collated, reformatted, de-identified, and analyzed using Stanford HIVdb program 7.0 and the 2009 World Health Organization (WHO) surveillance drug resistance mutations (SDRMs). Analyses were performed on subgroups of known treatment naives, treatment experienced, and seroconverters. There has been a decrease in overall rates of prevalent drug resistance mutations from 57.8% in 2004 to 21% in 2013. Dual and triple class resistance mutations have decreased from 32.7% in 2004 to 5.8% in 2013 and 16.4% to 1.2%, respectively. In treatment-naive individuals (

Background Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause a wide range of glomerular pathologies. In people with haemophilia, transfusion-associated infections with these viruses are common and definitive pathological diagnosis in this population is complicated by the difficulty of safely obtaining a renal biopsy. Membranous nephropathy (MN) is a common cause of adult onset nephrotic syndrome occurring in both primary and secondary forms. Primary MN is associated with podocyte autoantibodies, predominantly against phospholipase A2 receptor (PLA2R). Secondary disease is often associated with viral infection; however, infrequently with HIV or HCV. Distinguishing these entities from each other and other viral glomerular disease is vital as treatment strategies are disparate. Case presentation We present the case of a 48-year-old man with moderate haemophilia A and well-controlled transfusion-associated HCV and HIV coinfection who presented with sudden onset nephrotic range proteinuria. Renal biopsy demonstrated grade two membranous nephropathy with associated negative serum PLA2R testing. Light and electron microscopic appearances were indeterminant of a primary or secondary cause. Given his extremely stable co-morbidities, treatment with rituximab and subsequent angiotensin receptor blockade was initiated for suspected primary MN and the patient had sustained resolution in proteinuria over the following 18 months. Subsequent testing demonstrated PLA2R positive glomerular immunohistochemistry despite multiple negative serum results. Conclusions Pursuing histological diagnosis is important in complex cases of MN as the treatment strategies between primary and secondary vary significantly. Serum PLA2R testing alone may be insufficient in the presence of multiple potential causes of secondary MN.

International audience; Background: Global HIV-1 genetic diversity and evolution form a major challenge to treatment and prevention efforts. An increasing number of distinct HIV-1 recombinants have been identified worldwide, but their contribution to the global epidemic is unknown. We aimed to estimate the global and regional distribution of HIV-1 recombinant forms during 1990-2015.Methods: We assembled a global HIV-1 molecular epidemiology database through a systematic literature review and a global survey. We searched the PubMed, Embase (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) databases for HIV-1 subtyping studies published from Jan 1, 1990, to Dec 31, 2015. Unpublished original HIV-1 subtyping data were collected through a survey among experts in the field who were members of the WHO-UNAIDS Network for HIV Isolation and Characterisation. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. Countries were grouped into 14 regions and analyses were done for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV in each country to generate regional and global estimates of numbers and proportions of HIV-1 recombinants in each time period. The systematic review is registered with PROSPERO, CRD42017067164.Findings: Our global data collection yielded an HIV-1 molecular epidemiology database of 383 519 samples from 116 countries in 1990-2015. We found that the proportion of recombinants increased over time, both globally and in most regions, reaching 22·8% (7 978 517 of 34 921 639) of global HIV-1 infections in 2010-15. Both the proportion and the number of distinct CRFs detected increased over time to 16·7% and 57 CRFs in 2010-15. The global and regional distribution of HIV-1 recombinants was diverse and evolved over time, and we found large regional variation in the numbers (0-44 CRFs), types (58 distinct CRFs), and proportions (0-80·5%) of HIV-1 recombinants. Globally, CRF02_AG was the most prevalent recombinant, accounting for 33·9% (2 701 364 of 7 978 517) of all recombinant infections in 2010-15. URFs accounted for 26·7% (2 131 450 of 7 978 517), CRF01_AE for 23·0% (1 838 433), and other CRFs for 16·4% (1 307 270) of all recombinant infections in 2010-15. Although other CRFs accounted for small proportions of infections globally (

A 69-year-old man presented to the Emergency Department with 1 day of acute spontaneous vertigo, left-sided tinnitus and hearing loss. He had no otalgia, previous vertigo or hearing problems but did have a background of diabetes and hypertension. On examination, with fixation, there was no nystagmus, but without visual fixation (using Frenzel’s goggles), there was primary position left-beating nystagmus. The horizontal head-impulse test was negative, but his left Dix-Hallpike positional test was positive, provoking a paroxysm of up-beating, torsional nystagmus with vertigo. Otoscopy was normal with no vesicles. Weber’s test was positive to the right and Rinne’s was bilaterally negative. Smooth pursuit, saccades and cerebellar examinations were normal. Audiometry identified a left-sided profound and high-frequency and moderate-to-severe mid-frequency sensorineural hearing loss; right-ear audiometry identified only a mild high-frequency sensorineural hearing loss (figure 1A). He had acoustic reflexes in both ears at normal thresholds. Figure 1 (A) Asymmetric audiogram at initial presentation. Right ear shows a mild high-frequency sensorineural hearing loss, while the left ear shows a sloping mild-to-profound sensorineural hearing loss. (B) Left vestibular loss. Three-dimensional video head impulse at initial presentation shows isolated reduced left posterior semicircular canal vestibulo-ocular reflex gain (0.19) with catch-up saccades. (Gain values are listed to the top right of each individual head-impulse test.) (C) Repeat audiometry at 2 months. In comparison with the original audiogram, the right-ear results showed new upsloping severe-to-mild sensorineural hearing loss below 1 kHz and mild hearing loss above 1 kHz. The left-sided hearing has returned to normal at the low-to-mid frequencies after corticosteroid treatment. (D) Home audiometry over 45 days showing marked fluctuations in the right ear across the low-to-mid frequencies (≤1 kHz, red and orange traces). (E) The left ear shows little fluctuation in hearing loss. (F) Timeline of treatment. There was marked response in the left hearing loss, as …

We characterised the clinical and neuro-otological characteristics of patients with Susac syndrome. The medical records of 30 patients with Susac syndrome were reviewed for details of their clinical presentation and course, neuro-otological symptoms, investigation results including audiology and vestibular function tests, treatment and outcomes. Our findings demonstrate that 29 of our 30 patients with Susac syndrome developed neuro-otological symptoms such as hearing loss, disequilibrium, tinnitus or vertigo during their disease course. Hearing loss was the most common neuro-otological symptom occurring in 93% of patients. A rising configuration of low-frequency greater than the high-frequency sensorineural hearing loss was the most characteristic finding on audiological testing (37% of reviewed audiograms). Disproportionately poor speech discrimination was identified in 20% of cases, and one case demonstrated a retrocochlear pattern on electrophysiological testing. Four patients required hearing aids and a further two patients required a cochlear implant due to severe hearing loss. Two out of two treated patients had improvements in hearing after the prompt administration of corticosteroids, indicating the potential for recoverable hearing loss if relapses are treated early. Effects on vestibular function were variable in ten patients who were tested, with most showing preservation of function despite significant hearing loss. Neuro-otological symptoms in Susac syndrome are almost universal. In the correct clinical context, a rising configuration of low to high-frequency sensorineural hearing loss should prompt consideration of Susac syndrome. Treatment of inner ear symptoms in Susac syndrome requires further research as early immunotherapy may be beneficial.

In HIV-infected individuals on antiretroviral therapy (ART), latent HIV is enriched in CD4 T cells expressing immune checkpoint molecules, in particular programmed cell death-1 (PD-1). We therefore assessed the effect of blocking PD-1 on latency, both in vitro and in vivo.HIV latency was established in vitro following coculture of resting CD4+ T cells with myeloid dendritic cells. Expression of PD-1 was quantified by flow cytometry, and latency assessed in sorted PD-1high and PD-1low/-nonproliferating CD4+ memory T cells. The role of PD-1 in the establishment of latency was determined by adding anti-PD-1 (pembrolizumab) to cocultures before and after infection. In addition, a single infusion of anti-PD-1 (nivolumab) was administered to an HIV-infected individual on ART with metastatic melanoma, and cell-associated HIV DNA and RNA, and plasma HIV RNA were quantified.HIV latency was significantly enriched in PD-1high compared with PD-1low/- nonproliferating, CD4 memory T cells. Sorting for an additional immune checkpoint molecule, T-cell immunoglobulin domain and mucin domain-3, in combination with PD-1, further enriched for latency. Blocking PD-1 prior to HIV infection, in vitro, resulted in a modest but significant decrease in latently infected cells in all donors (n = 6). The administration of anti-PD-1 to an HIV-infected individual on ART resulted in a significant increase in cell-associated HIV RNA in CD4 T cells, without significant changes in HIV DNA or plasma HIV RNA, consistent with reversal of HIV latency.PD-1 contributes to the establishment and maintenance of HIV latency and should be explored as a target, in combination with other immune checkpoint molecules, to reverse latency.

Background Internationally, medical schools have long used a variety of approaches to develop hybrid Problem based learning (PBL) curricula. However, Team-based learning (TBL), has gained recent popularity in medical education. TBL maintains the advantages of small group teaching and learning, but in contrast to Problem-based learning (PBL), does not require large numbers of tutors. In 2016, TBL was introduced to Year 1 of the Sydney Medical Program (SMP).This study sought to compare students’ perceptions of using TBL in place of PBL. Methods Year 1 students (n = 169) completed three PBL and three TBL sessions during one of the following teaching blocks: Musculoskeletal (n = 56), Respiratory (n = 59) or Cardiovascular (n = 54). Student feedback following completion of each block of teaching was collected by questionnaire, using closed and open ended items. Data were analysed using descriptive statistics and thematic analysis. Results In total, 144/169 (85%) of participants completed a questionnaire regarding PBL, and 152/169 (90%) completed a similar questionnaire regarding TBL. The students found positive aspects of their TBL experience to include the smaller group size, the use of readiness assurance tests, immediate feedback from senior clinicians, and time efficiency. In PBL, students reported that variable expertise of tutors; limited direction; and large group size hindered their learning. Conclusions Overwhelmingly, students preferred TBL over PBL, as the optimal teaching strategy. Students found the structure and format of the TBL sessions more conducive to learning, engagement and participation than PBL sessions. Although the use of TBL required an instructional approach, needing direction from the tutor, it remained student-centred, generating a range of positive outcomes. Study results provide confidence to change from PBL to TBL within Year 1 and Year 2 of the SMP in 2017.

Background Rapid changes in medical practice have a large impact on the demands faced by educators in preparing students for future participation in a multifaceted healthcare workforce. Competencies required by today’s medical graduates encompass the ability to effectively collaborate, communicate and problem solve. The learning needs of medical students have also changed over time. Today’s medical students are highly interconnected, enjoying teamwork and collaborative practice, and desire continuous, explicit feedback. They want structured learning activities, with clear expectations, and enjoy a sense of accomplishment on their achievements. The conflation of these issues has seen many medical schools adopt the model of Team-based learning (TBL). Using the conceptual framework of communities of practice, we sought to qualitatively explore students’ and teachers’ experience of TBL in Year 1 of a graduate entry medical program. Methods Convenience sampling was used to select 169/350 (48%) Year 1 students who completed three TBL sessions. Each TBL session was facilitated by three senior clinicians. Following participation in the TBLs, students were invited to attend focus groups, and all facilitators (n = 9) were invited to attend interviews. A coding framework was developed to code the entire dataset, using the theoretical lens of communities of practice. Results 34/169 (20%) of students attended focus groups. Three facilitators (3/9, 33%) were interviewed. Students and facilitators felt the structure and organisation of TBL made students accountable for their learning and team contributions. The combined expertise and clinical experience of facilitators, with immediate feedback helped groups to work both independently and collaboratively. Facilitators found working with their peers in the TBLs to be a rewarding experience. Conclusions The community of practice found in the TBL classes, provided an enriching and rewarding learning environment that motivated students to build on their basic knowledge and apply what had been learnt. The interactions of experienced, senior clinicians as facilitators, sharing their expertise within a clinical context, prompted effective student engagement in learning and understanding. Our change in curriculum design and pedagogy will assist in preparing medical students for demands of the increasingly complex healthcare systems in which they will work.

Background Patients with thymoma with immunodeficiency (TWI)/Good’s syndrome characteristically have evidence of combined immunodeficiency including low or absent B-cells, hypogammaglobulinemia and defects in T-cell mediated immunity. These patients can present with common or opportunistic infections. Case presentation A 54-year-old female was diagnosed with cerebral toxoplasmosis. This occurred on a background of metastatic thymoma previously treated with chemotherapy and myasthenia gravis (MG) treated with mycophenolate mofetil, monthly intravenous immunoglobulin (IVIG) and pyridostigmine. She reported recurrent herpes zoster infection. The patient had clinical and radiological progression of cerebral infection despite completing standard induction and maintenance therapy with sulfadiazine and pyrimethamine. Investigations found a complete absence of B-cells and evidence for hypogammaglobulinemia which, together with evidence of defects in T-cell mediated immunity and thymoma, lead to a diagnosis of TWI/Good’s Syndrome. The patient has undergone prolonged high-dose therapy for toxoplasmosis and a reduction in immunosuppression with no evidence of recurrent toxoplasmosis or flare of MG. Conclusions TWI/Good’s Syndrome should be suspected in patients with thymoma and recurrent, persistent or unusual infections. If suspected serum immunoglobulins and lymphocyte subsets should be measured. These patients may need closer monitoring, higher dose and prolonged treatment of infections, and weaning of concurrent immunosuppression may be considered.

Introduction Rates of new HIV-1 diagnoses are increasing in Australia, with evidence of an increasing proportion of non-B HIV-1 subtypes reflecting a growing impact of migration and travel. The present study aims to define HIV-1 subtype diversity patterns and investigate possible HIV-1 transmission networks within Australia. Methods The Australian Molecular Epidemiology Network (AMEN) HIV collaborating sites in Western Australia, South Australia, Victoria, Queensland and western Sydney (New South Wales), provided baseline HIV-1 partial pol sequence, age and gender information for 4,873 patients who had genotypes performed during 2005–2012. HIV-1 phylogenetic analyses utilised MEGA V6, with a stringent classification of transmission pairs or clusters (bootstrap ≥98%, genetic distance ≤1.5% from at least one other sequence in the cluster). Results HIV-1 subtype B represented 74.5% of the 4,873 sequences (WA 59%, SA 68.4%, w-Syd 73.8%, Vic 75.6%, Qld 82.1%), with similar proportion of transmission pairs and clusters found in the B and non-B cohorts (23% vs 24.5% of sequences, p = 0.3). Significantly more subtype B clusters were comprised of ≥3 sequences compared with non-B clusters (45.0% vs 24.0%, p = 0.021) and significantly more subtype B pairs and clusters were male-only (88% compared to 53% CRF01_AE and 17% subtype C clusters). Factors associated with being in a cluster of any size included; being sequenced in a more recent time period (p3) was associated with being sequenced in a more recent time period (p = 0.05) and being male (p = 0.008). Conclusion This nationwide HIV-1 study of 4,873 patient sequences highlights the increased diversity of HIV-1 subtypes within the Australian epidemic, as well as differences in transmission networks associated with these HIV-1 subtypes. These findings provide epidemiological insights not readily available using standard surveillance methods and can inform the development of effective public health strategies in the current paradigm of HIV prevention in Australia.

Background In Australia, government-subsidised treatment of pulmonary arterial hypertension (PAH) is limited to monotherapy. Recent international guidelines advocate that initial combination therapy be considered for all symptomatic PAH patients. We sought to characterise “real-life” outcomes in PAH patients initiated on monotherapy. Methods We performed a retrospective analysis of 100 consecutive PAH patients at a single centre, who were commenced on monotherapy for PAH between 2004 and 2015. The composite clinical endpoint of ‘treatment failure’ was prospectively defined as (1) >15% fall in 6-minute walk distance on follow-up, (2) physician judgement of inadequate treatment response, (3) adverse drug effect requiring cessation, (4) death or transplantation. Results At initiation of therapy, mean age was 54 ± 18 years and underlying diagnoses included idiopathic (36%), connective tissue disease associated (37%), and congenital heart disease associated-PAH (25%). Baseline 6MWD was 360 ± 140 m and 75% were in either New York Heart Association functional class III or IV. Over median follow-up of 38 months (IQR 20–67), 62% of subjects met criteria for a clinical failure event. Median time to monotherapy failure was 24 months (95% CI 14–34) with death or transplantation being the most common clinical failure event. Estimated 1-, 3- and 5-yr survivals from time of treatment initiation were 92%, 75% and 66%. Conclusion The majority of patients failed initial monotherapy therapy within two years of treatment initiation. Broader access to approved PAH agents is needed to enable combination therapy in line with evidence based international guidelines.

BACKGROUND: Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial. METHODS: We did a single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications at the State University of New York Upstate Medical University (Syracuse, NY, USA). Eligible participants (aged ≥18 years) had active systemic lupus erythematosus fulfilling four or more of 11 diagnostic criteria defined by the American College of Rheumatology. We excluded patients with allergy or intolerance to sirolimus, patients with life-threatening manifestations of systemic lupus erythematosus, proteinuria, a urine protein to creatinine ratio higher than 0·5, anaemia, leucopenia, or thrombocytopenia. Patients received oral sirolimus at a starting dose of 2 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6–15 ng/mL. Patients were treated with sirolimus for 12 months. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. The primary efficacy endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Blood samples of 56 matched healthy individuals were obtained as controls for immunobiological outcomes monitored at each visit. The primary efficacy endpoint was assessed in all patients who completed 12 months of treatment, and all patients who received at least one dose of treatment were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00779194. FINDINGS: Between March 9, 2009, and Dec 8, 2014, 43 patients were enrolled, three of whom did not meet eligibility criteria. 11 of the 40 eligible patients discontinued study treatment because of intolerance (n=2) or non-compliance (n=9). SLEDAI and BILAG disease activity scores were reduced during 12 months of treatment in 16 (55%) of 29 patients who completed treatment. Mean SLEDAI score decreased from 10·2 (SD 5·6) at enrolment to 4·8 (4·5) after 12 months of treatment (p

Background Despite virally suppressive combination antiretroviral therapy (cART), some HIV-infected patients exhibit suboptimal CD4(+) T-cell recovery. This study aimed to determine the effect of intensification of cART with raltegravir or addition of hyperimmune bovine colostrum (HIBC) on CD4(+) T-cell count in such patients. Methods We randomized 75 patients to 4 treatment groups to receive raltegravir, HIBC, placebo, or both raltegravir and HIBC in a factorial, double-blind study. The primary endpoint was time-weighted mean change in CD4(+) T-cell count from baseline to week 24. T-cell activation (CD38(+) and HLA-DR(+)), plasma markers of microbial translocation (lipopolysaccharide, 16S rDNA), monocyte activation (soluble (s) CD14), and HIV-RNA (lowest level of detection 4 copies/mL) were monitored. Analysis was performed using linear regression methods. Results Compared with placebo, the addition of neither raltegravir nor HIBC to cART for 24 weeks resulted in a significant change in CD4(+) T-cell count (mean difference, 95% confidence interval [CI]: 3.09 cells/μL, -14.27; 20.45, P = .724 and 9.43 cells/μL, -7.81; 26.68, P = .279, respectively, intention to treat). There was no significant interaction between HIBC and raltegravir (P = .275). No correlation was found between CD4(+) T-cell count and plasma lipopolysaccharide, 16S rDNA, sCD14, or HIV-RNA. Conclusion The determinants of poor CD4(+) T-cell recovery following cART require further investigation. Clinical trials registration ClinicalTrials.gov identifier: NCT00772590, Australia New Zealand Clinical Trials Registry: ACTRN12609000575235.

Seven hundred and four HIV-1/2-positive, antiretroviral therapy (ART) naïve patients were screened for HTLV-1 infection. Antibodies to HTLV-1 were found in 32/704 (4.5%) of the patients. Each co-infected individual was matched with two HIV mono-infected patients according to World Health Organization clinical stage, age ±5 years and gender. Key clinical and laboratory characteristics were compared between the two groups. Mono-infected and co-infected patients displayed similar clinical characteristics. However, co-infected patients had higher absolute CD4+ T-cell counts ( P = 0.001), higher percentage CD4+ T-cell counts ( P < 0.001) and higher CD4/CD8 ratios ( P < 0.001). Although HIV plasma RNA viral loads were inversely correlated with CD4+ T-cell-counts in mono-infected patients ( P < 0.0001), a correlation was not found in co-infected individuals ( P = 0.11). Patients with untreated HIV and HTLV-1 co-infection show a dissociation between immunological and HIV virological markers. Current recommendations for initiating ART and chemoprophylaxis against opportunistic infections in resource-poor settings rely on more readily available CD4+ T-cell counts without viral load parameters. These guidelines are not appropriate for co-infected individuals in whom high CD4+ T-cell counts persist despite high HIV viral load states. Thus, for co-infected patients, even in resource-poor settings, HIV viral loads are likely to contribute information crucial for the appropriate timing of ART introduction.

This study assessed the relationship between changes in CD4 T-cell count, HIV Viral Load (VL) level and evolutionary patterns in Antiretroviral (ARV) resistance mutations of circulating HIV in those with persistent viraemia despite treatment. The study examined the dynamics of change in resistance mutations to explore potential predictors of evolution in the circulating virus over a prolonged period. Four longitudinal blood samples from 29 HIV-infected Australian patients at RPAH are analysed for the presence of genotypically resistant HIV virus. The subjects had CD4 cells counts (40-670 cells/mm(3)), VL levels (1.7-5.7 log(10) copies/ml), drug resistance mutations, and had been treated with ARV regimens for varying periods between February 1998 and June 2005 (i.e., 88 months). Parametric and nonparametric tests were used to examine changes in CD4 T-cell counts and VL levels, and in frequencies of mutations at different sample points. Nonparametric LOESS fitting curves were used to analyse changes in CD4 T-cell counts and VL levels. During the study period, changes in mean values of CD4 cell counts and VL levels in patients displaying an evolving genotypic resistance profile differed from those without evidence of an evolving mutational pattern; applied for both Reverse-Transcriptase (RT) and Protease (PR) gene profiles. In patients with Evolution-of-Resistance (EoR) at the RT site, there was a significant decrease in mean CD4 cell count during the first 36 months (-194 cells/mm(3), P=0.0466) but no significant change in the last 52 months or thereafter (-10 cells/mm(3), P=0.8464). Conversely, in patients with EoR at the PR site, there was no significant change in mean CD4 cell count during the first 36 months (-30 cells/mm(3), P=0.6187) but a significant decrease (-155 cells/mm(3), P=0.0348) thereafter. In patients without EoR at the RT site, there was no significant change in mean CD4 count during the first 36 months (-12 cells/mm(3), P=0.8371), however, a significant increase in mean CD4 cell count occurred thereafter (+242 cells/mm(3), P=0.0077). Similarly, in patients without EoR at the PR site there was no significant change in mean CD4 count during the first 36 months (-19 cells/mm(3), P=0.6647) and there was a significant increase in the last 52 months (+145 cells/mm(3), P=0.0348). The only significant decrease in mean value of VL levels occurred in patients without EoR associated with NRTIs thereafter (-1.33 log(10) copies/ml, P=0.0477), while no significant changes in mean value of VL levels in patients with/without EoR associated with any ARV drugs at any other time points (-0.65 to +0.15 log(10) copies/ml, P=0.1855 to 0.7958). Low CD4 cell counts (250 cells/mm(3)) and high VL levels (4.50 log(10) copies/ml) in the early stage of HIV infection, a significant decrease in CD4 cell counts during the first 36 months (-50 or more cells/mm(3)), and high frequencies of mutations during the first 36 months of antiretroviral regimen (3 mutations) emerged as potential predictive factors of EoR associated with NRTI/PRI agents thereafter. Stable VL in the first 36 months correlated with lack of lability of resistance mutations thereafter.

Objectives To assess the prevalence, distribution and clinical correlates of myocardial fibrosis, as detected by cardiac magnetic resonance (CMR), in systemic lupus erythematosus (SLE). Methods Forty-one subjects (average age 39 ± 12 years and 80% female) with SLE underwent CMR imaging at 1.5T, using late gadolinium enhancement (LGE) to quantify the area of myocardial fibrosis in the left ventricle (LV). Subjects also underwent transthoracic echocardiography (TTE) and exercise testing. Results LGE was detected in 15/41 subjects, 11 with localized LGE (15% LV mass). The commonest site of LGE was the interventricular septum, with all but one case demonstrating an intramural or inflammatory pattern. The mean age of the >15% LGE group (55 ± 15 years) was significantly higher than the 15% demonstrated a reduced E/A ratio of 0.9 ± 0.4 relative to the 15% LGE group. Conclusions Mid-wall myocardial fibrosis occurs frequently in SLE and is strongly associated with advancing subject age, but not with SLE duration or severity. Extensive LGE may be associated with diastolic dysfunction and impaired exercise capacity, although this may be an epiphenomenon of age. Cardiac magnetic resonance with quantitative assessment of LGE may provide a basis for cardiac risk stratification in SLE.

Inferior alveolar nerve blocks are commonly performed for dental anaesthesia. The procedure is generally safe with a low rate of complications. We report a patient with a reproducible, delayed-onset sensory deficit associated with contrast-enhancing lesions in the trigeminal nerve, pons and medulla following inferior alveolar nerve local anaesthesia. We propose that this previously undescribed condition is a form of Type IV hypersensitivity reaction.

Objectives: To investigate (i) differences in dietary fat and energy intake between those reporting and those not reporting fat redistribution syndrome (FRS), and (ii) the relationship between dietary fat, total energy intake, serum biochemistry and the clinical characteristics of the syndrome. Design: A cross-sectional study. Setting: Outpatient service of a tertiary referral hospital, Sydney, Australia. Patients and methods: Dietary intake, serum lipids and insulin resistance and body composition (fat-free mass, fat mass, waist-to-hip ratio; WHR) were determined in 100 HIV-positive patients whose FRS status was classified on the basis of self-report of body composition changes, verified by clinical examination. Results: There was no significant difference in total or saturated dietary fat intake when grouped by FRS status. There was no significant correlation between dietary saturated or total fat intake and the serum or body composition parameters measured. Total energy intake was higher in those patients reporting FRS (14 575 versus 12 283 kJ, P = 0.037) after adjustment for age, smoking and exercise status. Conclusion: There appears to be no relationship between either dietary saturated or total fat intake and the serum or body composition parameters characteristic of FRS; however, the total energy intake was significantly higher in those with FRS. The nature of the relationship between total energy intake and FRS (cause or effect) warrants further investigation.

Objectives: To identify risk factors for non-Hodgkin's lymphoma (NHL) in people with HIV infection. Design and setting: Case-control study in Sydney, Australia. Participants and methods: Two hundred and nineteen patients with AIDS-related NHL were compared with 219 HIV-infected controls without NHL, matched for CD4 positive cell count and date of specimen collection. Data on demographic, infectious, treatment-related and immunological factors were abstracted by medical record review. The association between demographic factors, sexually transmissible diseases, HIV-related opportunistic infections, anti-viral therapy, duration of immune deficiency and indices of immune stimulation and risk of NHL were derived for these groups. Results: In a multivariate model, there were two independent groups of predictors of NH risk. The first was duration of immunodeficiency, as measured by longer time since seroconversion (P for trend 0.008), and lower CD4 positive cell count 1 year prior to the time of NHL diagnosis (P for trend 0.009). The second predictor was B-cell stimulation, as indicated by higher serum globulin (a surrogate marker for serum immunoglobulin, Pfor trend 0.044) and HIV p24 antigenaemia [odds ratio (OR) for p24 positivity, 1.82; 95% confidence interval (CI), 1.15-2.88]. Indices of B-cell stimulation preceded the diagnosis of NHL by several years. Factors not related to NHL risk included clinical indices of Epstein-Barr virus infection and receipt of individual nucleoside analogue antiretroviral agents. Combination therapy with these agents was associated with a non-significant reduction in NHL risk (OR, 0.68; 95% CI, 0.39-1.18). Conclusions: Markers of long-standing immune deficiency and B-cell stimulation were associated with an increased risk of developing NHL. Unless the strongest risk factor for NHL, immune deficiency, can be reversed, NHL is likely to become proportionately more important as a cause of morbidity and mortality in people with HIV infection.

We report the case of a 30-year-old woman who failed to achieve diagnostic Western blot criteria for HIV-1 infection until 21 months after her initial presentation. This case highlights the importance of suspecting delayed HIV seroconversion in cases with persistently indeterminant Western blots.

Prolonged acute spontaneous vertigo can be secondary to acute vestibular neuritis or posterior circulation ischaemia. We present a 66-year-old man who first developed an acute vestibular syndrome with profound unilateral hearing loss 34 years ago. First treated as vestibular neuritis, he subsequently developed manifestations of Behcet’s disease, including mouth ulcers, genital ulcers and erythema nodosum over a period of 10 years. Subsequently, sudden sensorineural hearing loss affecting his only hearing ear responded to immunomodulation, confirming an autoimmune cause for the audiovestibular symptoms. This report serves as a reminder that vestibular neuritis seldom causes hearing loss; ischaemic, infective and autoimmune causes should be sought when an acute vestibular syndrome is accompanied by hearing impairment.

Bickerstaff's encephalitis is a syndrome of ophthalmoplegia, ataxia and impaired consciousness commonly associated with serum GQ1b antibodies. We describe a patient with seropositive Bickerstaff's encephalitis who did not respond either to plasma exchange or intravenous immunoglobulin but recovered following adjunct treatment with the anti-CD 20 monoclonal antibody, Rituximab. There was a concomitant reduction in serum GQ1b antibodies associated with improvement. Interestingly, GQ1b antibody was also detected in CSF. These findings have potentially significant clinical and immunopathological implications.

The 1858T allele of protein tyrosine phosphatase nonreceptor type 22 (PTPN22; R620W) exhibits one of the strongest and most consistent associations with sporadic autoimmune disease. Although autoimmunity is common in patients with primary antibody deficiency (PAD), it remains unknown whether its pathogenesis is similar when it arises in this context compared with in immunocompetent patients.We set out to determine whether the 1858T allele of PTPN22 was associated with PAD or with autoimmunity in the context of PAD.We genotyped rs2476601 (g.1858CT), a single nucleotide polymorphism encoding substitution of arginine for tryptophan in PTPN22 (R620W), in 193 patients with PAD and 148 control subjects from an Australian cohort. We also performed a subgroup analysis according to the presence of autoimmunity and B-cell phenotypes.C/T and T/T PTPN22 genotypes were more common in patients with PAD than in the matched control subjects (C/T, 18.1% vs 9.5%; T/T, 1.04% vs 0.6%). The T allele was associated with an increased risk of PAD relative to control subjects (odds ratio, 2.10; 95% CI, 1.11-4.00). The distribution of genotypes in control subjects was similar to those reported previously and did not deviate significantly from Hardy-Weinberg equilibrium. We found a strong association between the 1858T allele and PAD with coexistent autoimmune diseases. In patients with PAD and autoimmunity, 16 (43.2%) of 37 had at least one T allele of PTPN22 compared with 27 (17.3%) of 156 with the C/C genotype (P=.0014; odds ratio, 3.64; 95% CI, 1.68-7.88). We found no evidence that this effect was mediated by enrichment of CD21low B cells.The 1858T PTPN22 allele is strongly associated with autoimmunity in patients with PAD.

Susac's syndrome is the clinical triad of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss (Susac 1994) [1]. It occurs predominantly in young females and is believed to be an immune-mediated endotheliopathy of small vessels of the brain, retina and cochlea (Neumayer et al. 2009) [2]. Early, aggressive, and sustained immunosuppressive therapy has been recommended for Susac's syndrome and anecdotal evidence has suggested a therapeutic role for monoclonal antibodies (Rennebohm et al. 2008, Lee and Amezcua 2009) [3,4]. We report a case of Susac's syndrome in which the patient improved immediately after tumour necrosis factor (TNF) inhibition with the monoclonal antibody, infliximab.

Our aim was to compare the assault characteristics of victims presenting to a sexual assault service who were prescribed HIV post-exposure prophylaxis (HIV PEP) with those not prescribed HIV PEP. A retrospective review was carried out of the medical records of victims who were seen over a 12-month period in 1999/2000. HIV PEP may have been potentially appropriate for 117 victims, of whom nine (7.7%) were prescribed PEP (eight women, one man). There was a trend for prescription of PEP to depend on the type of assault, with those suffering anal penetration most likely to be prescribed PEP, followed by those with vaginal, and then oral penetration ( P=0.08). Those who gave a history of oral or vaginal mucosal contact with ejaculate were more likely to receive PEP compared with those in whom ejaculation occurred at a non-mucosal site ( P=0.03). Most prescribed PEP regimens involved three antiretroviral drugs. In this study, HIV PEP, when prescribed, was in accord with existing guidelines. Future studies should aim to better document HIV seroconversions in victims of sexual assault and HIV seroprevalence in assailants.

Objectives To analyse clinical features and predictors of survival for AIDS-related non-Hodgkin's lymphoma (NHL) in the era of highly active antiretroviral therapy (HAART), compared to earlier in the HIV epidemic. Methods All AIDS-NHL cases diagnosed at three inner Sydney hospitals caring for people with AIDS during 1985–2001 were identified through medical record searches. Demographic, clinical, immunological and histopathological information was recorded. Year of NHL diagnosis was grouped into three periods, corresponding to whether monotherapy (1985–1991), dual therapy (1992–1995) or HAART (1996–2001) was the main treatment for HIV infection. Statistical comparisons were made between the pre-HAART and post-HAART eras. Results Three hundred cases of AIDS-NHL were identified. Divergent trends were identified for systemic and primary central nervous system (CNS) NHL. For systemic NHL, the CD4 count at NHL diagnosis increased markedly to 208 cells/μL in the post-HAART era (P=0.014) and there was a trend towards presentation as the first AIDS-defining illness (69%, P=0.053), and as earlier stage NHL disease (42%, P=0.048). Median survival time increased from 4.2 months in 1985–1991 to 19 months in the post-HAART era (P

It is often uncertain whether deaths that occur during active treatment for complications of AIDS result from diagnostic or therapeutic failure. Accurate diagnosis of infections is particularly important, and has relevance not only for the patient but also to partners, relatives, hospital staff and other patients. In the absence of adequate physical facilities and in view of the lack of success in obtaining formal autopsies in patients dying with AIDS, a limited autopsy protocol was devised for routine application at our hospital, beginning in 1989. The major aim of this protocol was to enable the safe collection of diagnostic material from patients who died despite active therapy, to ascertain unrecognized conditions and confirm existing diagnoses. We present findings from the first 16 limited autopsies which resulted in 12 additional diagnoses and a revision of the principal cause of death in 7 cases.

This study was a cross-sectional study of 122 HIV-positive subjects to determine the prevalence and predictors of weight loss in the era of highly active antiretroviral therapy (HAART). Forty per cent reported lipodystrophy, 40% had documented weight loss (mean 6.6 kg). Mean intake 13400 kJ (118% of estimated requirements calculated using the Harris-Benedict equation). One hundred (82%) were taking antiretroviral therapy. Using forward stepwise logistic regression analysis only viral load (VL) was significantly associated with weight loss when intake, CD4 T-cell count, lipodystrophy, and age were entered into the model with VL (log copies/mL). Every one log increase in HIV VL was associated with an odds of weight loss of 1.58 ( P=0.0008). Weight loss is still common in the HAART era. HIV VL was the most significant predictor of weight loss in this sample. Inadequate dietary intake and self-reported lipodystrophy were not related to weight loss in this population.

1. To determine if resting energy expenditure (REE) adjusted for body composition is elevated in HIV-positive males when compared with healthy controls in the era of highly active antiretroviral therapy. 2. To examine the accuracy of prediction equations for estimating REE in people with HIV. 3. To determine if REE adjusting for body composition is significantly different between those HIV-positive subjects reporting lipodystrophy (LD) or weight loss (or=5%) and those who are weight stable when compared to controls.Cross-sectional study.Tertiary referral hospital HIV unit and an outpatient clinic specializing in HIV care.HIV-positive males (n=70) and healthy male controls (n=16).REE was measured using indirect calorimetry. Body composition was assessed using bioelectrical impedance analysis.1. REE when adjusted for fat-free mass and fat mass using the general linear model (analysis of covariance) was greater in HIV-positive subjects than controls (7258+/-810 kJ, n=70 vs 6615+/-695 kJ, n=16, P0.05). 2. The Harris and Benedict, Schofield, Cunningham and the two equations previously published by Melchior and colleagues in HIV-positive subjects all gave an estimate of REE significantly different from the measured REE in the HIV-positive subjects, therefore a new prediction equation was developed. The inability of the published equations to predict REE in the different HIV-positive subgroups reflected the heterogeneity in body composition. 3. REE adjusted for fat-free and fat mass was significantly greater in the both the HIV patients who were weight stable and those with lipodystrophy compared with the healthy controls.REE is significantly higher in HIV-positive males when compared with healthy controls. Body composition abnormalities common in HIV render the use of standard prediction equations for estimating REE invalid. When measuring REE in HIV-positive males adjustment steps should include fat-free and fat mass.

This randomized, prospective study compared three treatments, nandrolone decanoate (ND), megestrol acetate (MA) or dietary counselling, for managing human immunodeficiency syndrome (HIV) associated weight loss. It was centred on a Tertiary referral hospital, Sydney, Australia. Fifteen patients were randomized to receive ND (100 mg/fortnight), or MA (400 mg/day) or dietary counselling for 12 weeks. Those patients randomized to dietary counselling were further randomized to receive nandrolone or megestrol after completing the dietary counselling arm. Weight, fat free mass (FFM), percentage body fat mass (FM), dietary intake and appetite were assessed before commencing and at the completion of each treatment arm. Weight increased significantly in all treatment arms (dietary counselling 1.13 kg +/- 0.36, nandrolone 4.01 kg +/- 1.68, megestrol 10.20 kg +/- 4.51, p < 0.05 paired t-test). FFM increased significantly in patients receiving ND (3.54 +/- 1.98 kg, p=0.001) and those receiving MA (2.76 +/- 0.55 kg, p=0.002), whereas the change in those receiving dietary counselling alone was not significant. Percentage body fat mass increased significantly only in those receiving MA (7.77 +/- 4.85%, p=0.049). The change in weight and percentage body fat mass was significantly greater in those receiving MA than the other two treatment arms. The increase in FFM was significantly greater in both the nandrolone and megestrol arms than the dietary counselling arm. It was concluded that ND and MA both resulted in an increase in FFM greater than dietary counselling alone. Megestrol produced a significantly greater increase in weight, percentage fat mass, intake and appetite than did the other two treatment arms, suggesting it may be the preferred agent, particularly in a palliative care setting in which weight, appetite and intake increase are desirable without regard to the composition of the body. The long-term use of these agents in people with HIV should be reviewed in the context of improved survival on highly active antiretroviral therapy regimens.

Background: In HIV infection T-cell dysfunction resulting in anergy and hypersensitivity reactions precedes T-cell depletion. A shift in the cytokine profile from a type 1 to a type 2 response has been postulated. Objective: We sought to examine the cytokine expression patterns in HIV infection and the relationship to allergy, stage of HIV disease, and other laboratory parameters. Methods: A cross-sectional analysis of IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p35, IL-13, and IFN-γ mRNA expression in PBMCs by noncompetitive dot-blot PCR was performed on blood obtained from 18 HIV-infected subjects. Delayed-type hypersensitivity multitests to detect anergy, skin prick testing and in vitro assay for specific IgE antibodies, assay for total IgE, and enumeration of eosinophils, CD4 + , and CD8 + T cells were also performed on all subjects. Results: We found evidence of a decline in type 1 cytokines (IL-2, IL-12p35, and IFN-γ) associated with AIDS, CD4 + T cells less than 200/μL, anergy, and atopy, although this only reached statistical significance in anergy. There was no associated significant alteration in type 2 cytokines. Conclusions: This is the first report of an association between low constitutive in vivo expression of IL-12 mRNA and anergy, which supports earlier data from in vitro stimulation studies. The presence of atopy was associated with a more global reduction in cytokine expression. Because the decline in type 1 cytokines was not accompanied by a similar decline in type 2 cytokines, this does suggest a shift in the type 1/type 2 balance. (J Allergy Clin Immunol 1999;103:833-42.)

A diverse range of services were developed in NSW in response to the emerging HIV epidemic. These services included innovative multidisciplinary service models of care most of which have been durable. Allied health teams and ancillary services funded by non-government organisations have played a vital role in delivering care and support in the community. A consistency of approach to treatment across the health sector has been reinforced through continuing education activities and credentialing of antiretroviral-drug prescribers. This investment in care and treatment has resulted in reduced hospital bed use. High levels of treatment uptake over many years are likely to have a favourable impact on transmission rates thus contributing to the stability of the epidemic in NSW.

NSW has been recognised internationally for achieving a sustained, stable rate of HIV infection since 2000. An early mobilisation by communities initially at risk of HIV – gay men, sex workers and injecting drug users – resulted in rapid behaviour change and provided the basis for a continuing cooperative partnership with government, health service providers and researchers. This special issue of the NSW Public Health Bulletin describes the current response to HIV in NSW. Experts from diverse disciplinary and professional fields offer perspectives on the epidemiology, morbidity and impacts of HIV, current prevention challenges including with Aboriginal communities and people from culturally and linguistically diverse backgrounds, models for the diagnosis, care and treatment of HIV, and the legislative protection of public health and those who are living with HIV. The NSW experience demonstrates that the sustained cooperation of those affected, together with the efforts of government, health service providers and researchers, can achieve HIV control.

One hundred and sixty-one Australian patients with hereditary bleeding disorders comprising hemophilia A (120), hemophilia B (18), von Willebrand's disease (16), and seven symptomatic female hemophilia A or B carriers were screened for clinical and serological evidence of exposure to HTLV-IM/LAV/ARV/HIV infection. During the previous five years (1979–1984) they had been treated almost exclusively with blood products derived from Australian voluntary donors. The prevalence of HTLV-III antibodies in 1985 was 45%, with the highest frequency being in those with severe hemophilia A (78%) and the lowest in patients with hemophilia B (6%). Antibody positivity correlated with a reduced absolute T helper (T4) cell numbers and/or an inverted T4:T8 ratio. Lymphadenopathy was detected in 23 subjects but only 13 had an abnormal T cell ratio. Comparison of seropositivity and T4:T8 ratios in 32 patients studied in 1983 and again in 1985 suggested that T4 cell deficiency reflected HTLV-III exposure rather than being a predisposing factor for infection with the virus. Individual patients showed considerable fluctuation in T cell subsets over a 12 month period of follow-up, but as a population there was a slight trend with time towards diminishing T4:T8 ratio only in the antibody positive hemophilia A patients of mild to moderate severity. Three (2%) of the 161 patients screened to date have developed confirmed AIDS with fatal outcome. Following the introduction of rigid exclusion criteria for donors and heat treatment of Australian lyophilised concentrates in late 1984, no antibody negative subjects have seroconverted. To date none of 15 regular sexual partners of antibody positive patients have been consistently seropositive and four clinically well, antibody negative babies have been born to antibody positive fathers.

Antibodies to the species-specific phenolic glycolipid (PGL-1) of Mycobacterium leprae and a crude M. leprae sonicate were measured by ELISA in sera from newly diagnosed and treated leprosy patients from Sydney and Nepal. IgM anti-PGL-1 antibodies were present in 88-90% of untreated patients at the lepromatous pole of the clinical spectrum and 35-55% of those at the tuberculoid pole. In treated patients with either form of the disease, IgM anti-PGL-1 antibodies were within the normal range or minimally elevated. In contrast, high levels of IgG anti-PGL-1 antibodies were detected in both treated and untreated patients. Neither IgM nor IgG anti-PGL-1 antibodies were elevated in sera from Mantoux negative controls and only one out of 15 sera from patients with untreated tuberculosis contained significant amounts of antibody. Comparison of the data from the anti-PGL-1 assay with the antibody response to a crude M. leprae sonicate revealed that the latter assay yielded more variable results and discriminated less well between lepromatous and tuberculoid subjects and between untreated patients and those on therapy. Thus the IgM anti-PGL-1 response signifies the presence of active disease, particularly in multi-bacillary cases, and has the potential to be used not only to monitor the response of these patients to therapy, but also to detect subclinical leprosy in high-risk groups such as the relatives of patients with lepromatous disease.

Two lambda gt11 recombinant clones, JKL2 and JKL15, each containing an insert coding for part of the highly immunogenic 70-kilodalton (kDa) protein antigen, were isolated from a Mycobacterium leprae genomic library by immunoscreening with the monoclonal antibody L7. Clone JKL2 contained the largest insert, 2.3 kilobase pairs. Nonoverlapping fragments of this insert were used as probes and showed strong hybridization to a number of Mycobacterium tuberculosis-lambda gt11 recombinants producing proteins recognized by an anti-M. tuberculosis 71-kDa monoclonal antibody, IT11. One clone from a recombinant Mycobacterium bovis library was also characterized by using L7, and the insert from this clone, B5bt, hybridized strongly to the M. leprae probes as well. The nucleotide sequence of the 1,037-base-pair coding region of the JKL2 M. leprae clone which encodes the carboxy-terminal half of the 70-kDa protein had extensive homology with genes from a number of species. In all cases, these genes, including the recently described Ag63 and Ag361 of Plasmodium falciparum, were found to be members of the heat shock protein 70 (hsp 70) family of genes. At the amino acid level, homology was maximal between amino acids 83 through 107 and 159 through 184, which showed extreme conservation (92 and 85% identity) with Escherichia coli DnaK amino acids 386 through 409 and 460 through 485, respectively, and was 51% homologous over the entire coding region (amino acids 1 through 344 of JKL2). In contrast, amino acids 129 through 158 had maximal homology with the phylogenetically more distant Xenopus laevis hsp70. Homology declined substantially in the carboxy-terminal 34 amino acids. The predicted ATP-binding functional activity of the 70-kDa antigen from M. bovis was confirmed with affinity purification of the antigen by binding to ATP-agarose and elution with ATP. In view of the conservation of sequences between these mycobacterial antigens and mammalian endogenous cellular enzymes, further evaluation of these molecules in vivo may aid in understanding tolerance to self-antigens as well as provide potentially useful immunodiagnostic reagents.

Background Multicentric Castleman’s disease (MCD) is a pre-malignancy that presents with lymphadenopathy and features of systemic inflammation. Human immunodeficiency virus (HIV)-associated MCD is associated with human herpesvirus-8 (HHV-8) infection. If untreated MCD has a relapsing and remitting course that is eventually fatal. Case presentation A 67-year-old man had six hospital admissions over 20 months characterised by fever, urinary frequency and CRP >100 mg/L. The final admission was complicated by hypotension requiring intensive care unit admission and ionotropic support. His history included HIV and Hepatitis B virus (HBV) co-infection on suppressive therapy. Each presentation was managed as presumed urosepsis with use of empirical antibiotics, however numerous blood and urine cultures failed to identify a pathogen. A bone-marrow aspirate and trephine found no evidence of haematological malignancy. A positron emission tomography scan found active lymph nodes, one of which was biopsied and found to contain the plasma-cell variant of Castleman’s disease. Ultimately the cause for the recurrent presentations was attributed to progressive MCD. The patient received rituximab monotherapy and has had no further related admissions. Conclusions MCD should be considered in patients with chronic HIV infection presenting with recurrent sepsis-like episodes and/or vasodilatory shock, particularly if no pathogen is identified or lymphadenopathy is evident.

BACKGROUND: Global genetic diversity of HIV-1 is a major challenge to the development of HIV vaccines. We aimed to estimate the regional and global distribution of HIV-1 subtypes and recombinants during 1990-2015. METHODS: We searched PubMed, EMBASE (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) for HIV-1 subtyping studies published between Jan 1, 1990, and Dec 31, 2015. We collected additional unpublished HIV-1 subtyping data through a global survey. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. We grouped countries into 14 regions and analysed data for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of HIV-1 subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV (PLHIV) in each country to generate regional and global estimates of HIV-1 diversity in each time period. The primary outcome was the number of samples designated as HIV-1 subtypes A, B, C, D, F, G, H, J, K, CRFs, and URFs. The systematic review is registered with PROSPERO, number CRD42017067164. FINDINGS: This systematic review and global survey yielded 2203 datasets with 383 519 samples from 116 countries in 1990-2015. Globally, subtype C accounted for 46·6% (16 280 897/34 921 639 of PLHIV) of all HIV-1 infections in 2010-15. Subtype B was responsible for 12·1% (4 235 299/34 921 639) of infections, followed by subtype A (10·3%; 3 587 003/34 921 639), CRF02_AG (7·7%; 2 705 110/34 921 639), CRF01_AE (5·3%; 1 840 982/34 921 639), subtype G (4·6%; 1 591 276/34 921 639), and subtype D (2·7%; 926 255/34 921 639). Subtypes F, H, J, and K combined accounted for 0·9% (311 332/34 921 639) of infections. Other CRFs accounted for 3·7% (1 309 082/34 921 639), bringing the proportion of all CRFs to 16·7% (5 844 113/34 921 639). URFs constituted 6·1% (2 134 405/34 921 639), resulting in recombinants accounting for 22·8% (7 978 517/34 921 639) of all global HIV-1 infections. The distribution of HIV-1 subtypes and recombinants changed over time in countries, regions, and globally. At a global level during 2005-15, subtype B increased, subtypes A and D were stable, and subtypes C and G and CRF02_AG decreased. CRF01_AE, other CRFs, and URFs increased, leading to a consistent increase in the global proportion of recombinants over time. INTERPRETATION: Global and regional HIV diversity is complex and evolving, and is a major challenge to HIV vaccine development. Surveillance of the global molecular epidemiology of HIV-1 remains crucial for the design, testing, and implementation of HIV vaccines. FUNDING: None. ispartof: LANCET INFECTIOUS DISEASES vol:19 issue:2 pages:143-155 ispartof: location:United States status: published