Rate of response to initial antiretroviral therapy according to level of pre-existing HIV-1 drug resistance detected by next-generation sequencing in the strategic timing of antiretroviral treatment (START) study.

OBJECTIVES: The main objective of this analysis was to evaluate the impact of pre-existing drug resistance by next-generation sequencing (NGS) on the risk of treatment failure (TF) of first-line regimens in participants enrolled in the START study. METHODS: Stored plasma from participants with entry HIV RNA >1000 copies/mL were analysed using NGS (llumina MiSeq). Pre-existing drug resistance was defined using the mutations considered by the Stanford HIV Drug Resistance Database (HIVDB v8.6) to calculate the genotypic susceptibility score (GSS, estimating the number of active drugs) for the first-line regimen at the detection threshold windows of >20%, >5%, and >2% of the viral population. Survival analysis was conducted to evaluate the association between the GSS and risk of TF (viral load >200 copies/mL plus treatment change). RESULTS: Baseline NGS data were available for 1380 antiretroviral therapy (ART)-naïve participants enrolled over 2009-2013. First-line ART included a non-nucleoside reverse transcriptase inhibitor (NNRTI) in 976 (71%), a boosted protease inhibitor in 297 (22%), or an integrase strand transfer inhibitor in 107 (8%). The proportions of participants with GSS <3 were 7% for >20%, 10% for >5%, and 17% for the >2% thresholds, respectively. The adjusted hazard ratio of TF associated with a GSS of 0-2.75 versus 3 in the subset of participants with mutations detected at the >2% threshold was 1.66 (95% confidence interval 1.01-2.74; p = 0.05) and 2.32 (95% confidence interval 1.32-4.09; p = 0.003) after restricting the analysis to participants who started an NNRTI-based regimen. CONCLUSIONS: Up to 17% of participants initiated ART with a GSS <3 on the basis of NGS data. Minority variants were predictive of TF, especially for participants starting NNRTI-based regimens.

HIV: the changing paradigm.

The past four decades have seen enormous progress in the diagnosis and management of human immunodeficiency virus (HIV) infection. There have been significant advances spanning the approval of the first antiretroviral agents, the advent of combination antiretroviral therapy to single tablet regimens with minimal toxicity. Although these remarkable developments have on the surface led to the 'end of AIDS', there are still key populations being left behind. This clinical update will describe the diagnosis and management of HIV, and the changing paradigms that have seen HIV transform from a life-limiting condition to a manageable chronic disease over a few decades.

Subtype-specific differences in transmission cluster dynamics of HIV-1 B and CRF01_AE in New South Wales, Australia.

INTRODUCTION: The human immunodeficiency virus 1 (HIV-1) pandemic is characterized by numerous distinct sub-epidemics (clusters) that continually fuel local transmission. The aims of this study were to identify active growing clusters, to understand which factors most influence the transmission dynamics, how these vary between different subtypes and how this information might contribute to effective public health responses. METHODS: We used HIV-1 genomic sequence data linked to demographic factors that accounted for approximately 70% of all new HIV-1 notifications in New South Wales (NSW). We assessed differences in transmission cluster dynamics between subtype B and circulating recombinant form 01_AE (CRF01_AE). Separate phylogenetic trees were estimated using 2919 subtype B and 473 CRF01_AE sequences sampled between 2004 and 2018 in combination with global sequence data and NSW-specific clades were classified as clusters, pairs or singletons. Significant differences in demographics between subtypes were assessed with Chi-Square statistics. RESULTS: We identified 104 subtype B and 11 CRF01_AE growing clusters containing a maximum of 29 and 11 sequences for subtype B and CRF01_AE respectively. We observed a > 2-fold increase in the number of NSW-specific CRF01_AE clades over time. Subtype B clusters were associated with individuals reporting men who have sex with men (MSM) as their transmission risk factor, being born in Australia, and being diagnosed during the early stage of infection (p < 0.01). CRF01_AE infections clusters were associated with infections among individuals diagnosed during the early stage of infection (p < 0.05) and CRF01_AE singletons were more likely to be from infections among individuals reporting heterosexual transmission (p < 0.05). We found six subtype B clusters with an above-average growth rate (>1.5 sequences / 6-months) and which consisted of a majority of infections among MSM. We also found four active growing CRF01_AE clusters containing only infections among MSM. Finally, we found 47 subtype B and seven CRF01_AE clusters that contained a large gap in time (>1 year) between infections and may be indicative of intermediate transmissions via undiagnosed individuals. CONCLUSIONS: The large number of active and growing clusters among MSM are the driving force of the ongoing epidemic in NSW for subtype B and CRF01_AE.

Increased HIV Subtype Diversity Reflecting Demographic Changes in the HIV Epidemic in New South Wales, Australia.

Changes over time in HIV-1 subtype diversity within a population reflect changes in factors influencing the development of local epidemics. Here we report on the genetic diversity of 2364 reverse transcriptase sequences from people living with HIV-1 in New South Wales (NSW) notified between 2004 and 2018. These data represent >70% of all new HIV-1 notifications in the state over this period. Phylogenetic analysis was performed to identify subtype-specific transmission clusters. Subtype B and non-B infections differed across all demographics analysed (p < 0.001). We found a strong positive association for infections among females, individuals not born in Australia or reporting heterosexual transmission being of non-B origin. Further, we found an overall increase in non-B infections among men who have sex with men from 50 to 79% in the last 10 years. However, we also found differences between non-B subtypes; heterosexual transmission was positively associated with subtype C only. In addition, the majority of subtype B infections were associated with clusters, while the majority of non-B infections were singletons. However, we found seven non-B clusters (≥5 sequences) indicative of local ongoing transmission. In conclusion, we present how the HIV-1 epidemic has changed over time in NSW, becoming more heterogeneous with distinct subtype-specific demographic associations.

The benefit of immediate compared with deferred antiretroviral therapy on CD4+ cell count recovery in early HIV infection.

OBJECTIVE: To assess the impact of immediate vs. deferred antiretroviral therapy (ART) on CD4 recovery among individuals early in HIV infection. DESIGN: Using serologic markers of early infection together with self-reported dates of infection and HIV diagnosis, ART-naive participants who were randomized to immediate vs. deferred ART in the Strategic Timing of Antiretroviral Treatment trial were classified into subgroups of duration of HIV infection at baseline. CD4 cell count recovery over follow-up according to duration of HIV infection was investigated. METHODS: Three subgroups were defined: first, infected 6 months or less (n = 373); second, infected 6-24 months (n = 2634); and third, infected 24 months or longer (n = 1605). Follow-up CD4, CD8, and CD4 : CD8 ratio for the immediate and deferred ART groups were compared by subgroup using linear models. For the deferred ART group, decline to CD4 less than 350 cells/µl or AIDS according to infection duration was compared using time-to-event methods. RESULTS: Follow-up CD4 cell count differences (immediate minus deferred) were greater for those recently infected (+231 cells/µl) compared with the two other subgroups (202 and 171 cells/µl; P < 0.001). CD4 : CD8 ratio treatment differences varied significantly (P < 0.001) according to duration of infection. In the deferred ART group, decline to CD4 less than 350 cells/µl or AIDS was greater among those recently infected (16.1 vs. 13.2 and 10.5 per 100 person years for those infected 6-24 and ≥24 months; P = 0.002). CONCLUSION: In this randomized comparison of immediate vs. deferred ART, the CD4 cell count difference was greatest for those recently infected with HIV, emphasizing the importance of immediate ART initiation.

Limited Sustained Local Transmission of HIV-1 CRF01_AE in New South Wales, Australia.

Australia's response to the human immunodeficiency virus type 1 (HIV-1) pandemic led to effective control of HIV transmission and one of the world's lowest HIV incidence rates-0.14%. Although there has been a recent decline in new HIV diagnoses in New South Wales (NSW), the most populous state in Australia, there has been a concomitant increase with non-B subtype infections, particularly for the HIV-1 circulating recombinant form CRF01_AE. This aforementioned CRF01_AE sampled in NSW, were combined with those sampled globally to identify NSW-specific viral clades. The population growth of these clades was assessed in two-year period intervals from 2009 to 2017. Overall, 109 NSW-specific clades were identified, most comprising pairs of sequences; however, five large clades comprising ≥10 sequences were also found. Forty-four clades grew over time with one or two sequences added to each in different two-year periods. Importantly, while 10 of these clades have seemingly discontinued, the remaining 34 were still active in 2016/2017. Seven such clades each comprised ≥10 sequences, and are representative of individual sub-epidemics in NSW. Thus, although the majority of new CRF01_AE infections were associated with small clades that rarely establish ongoing chains of local transmission, individual sub-epidemics are present and should be closely monitored.

Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study.

BACKGROUND: Evidence on viral load and HIV transmission risk in HIV-serodiscordant male homosexual couples is limited to one published study. We calculated transmission rates in couples reporting condomless anal intercourse (CLAI), when HIV-positive partners were virally suppressed, and daily pre-exposure prophylaxis (PrEP) was not used by HIV-negative partners. METHODS: In the Opposites Attract observational cohort study, serodiscordant male homosexual couples were recruited from 13 clinics in Australia, one in Brazil, and one in Thailand. At study visits, HIV-negative partners provided information on sexual behaviour and were tested for HIV and sexually transmitted infections; HIV-positive partners had HIV viral load tests, CD4 cell count, and sexually transmitted infection tests done. Viral suppression was defined as less than 200 copies per mL. Linked within-couple HIV transmissions were identified with phylogenetic analysis. Incidence was calculated per couple-year of follow-up, focusing on periods with CLAI, no use of daily PrEP, and viral suppression. One-sided upper 95% CI limits for HIV transmission rates were calculated with exact Poisson methods. FINDINGS: From May 8, 2012, to March 31, 2016, in Australia, and May 7, 2014, to March 31, 2016, in Brazil and Thailand, 358 couples were enrolled. 343 couples had at least one follow-up visit and were followed up for 588·4 couple-years. 258 (75%) of 343 HIV-positive partners had viral loads consistently less than 200 copies per mL and 115 (34%) of 343 HIV-negative partners used daily PrEP during follow-up. 253 (74%) of 343 couples reported within-couple CLAI during follow-up, with a total of 16 800 CLAI acts. Three new HIV infections occurred but none were phylogenetically linked. There were 232·2 couple-years of follow-up and 12 447 CLAI acts in periods when CLAI was reported, HIV-positive partners were virally suppressed, and HIV-negative partners did not use daily PrEP, resulting in an upper CI limit of 1·59 per 100 couple-years of follow-up for transmission rate. INTERPRETATION: HIV treatment as prevention is effective in men who have sex with men. Increasing HIV testing and linking to immediate treatment is an important strategy in HIV prevention in homosexual men. FUNDING: National Health and Medical Research Council; amfAR, The Foundation for AIDS Research; ViiV Healthcare; and Gilead Sciences.

Early Treatment of Primary HIV Infection Is Associated with Decreased Mortality.

The aim of this study was to understand factors associated with increased mortality in a cohort of primary HIV infection (PHI) in New South Wales (NSW) over three decades. Six hundred and two patients with PHI were enrolled from 1984 to 2009. Probabilistic data linkage was performed to NSW Registry of births deaths and marriages and Australian Bureau of Statistics mortality database. Mortality was measured by crude death rate. Pre highly active antiretroviral therapy (pre-HAART) era was defined as before January 1, 1997. A Cox proportional hazard model was used to identify factors associated with death. One hundred and thirty-eight deaths occurred during 6,223 person years (PY) follow-up. Overall crude death rate was 2.2 per 100 PY (95% confidence interval [CI], 1.9-2.6), 3.6 (95% CI, 3.1-4.3)in pre-HAART era and 0.20 (95% CI, 0.08-0.47) in post-HAART era. AIDS was the most frequent cause of death (52%, 72/138), all occurring in the pre-HAART era. Of non-AIDS deaths, the leading known cause was non-AIDS cancer 8% (11/138) followed by suicide 4% (6/138). On multivariate analysis, estimated date of infection in pre-HAART era and time to commencement of ART greater than 1 year post diagnosis were more likely to be associated with death (p < .05). Mortality in PHI has decreased significantly in the post-HAART era. Non-AIDS deaths due to malignancy and suicide are emerging as leading causes in this population in the post-HAART era. Time to starting ART greater than 1 year was associated with increased mortality.

Comparison of Self-report to Biomarkers of Recent HIV Infection: Findings from the START Trial.

Identifying individuals with recent HIV infection is critical to research related to viral reservoirs, outbreak investigations and intervention applications. A multi-assay algorithm (MAA) for recency of infection was used in conjunction with self-reported date of infection and documented date of diagnosis to estimate the number of participants recently infected in the Strategic Timing of AntiRetroviral Treatment (START) trial. We tested samples for three groups of participants from START using a MAA: (1) 167 individuals who reported being infected ≤ 6 months before randomization; (2) 771 individuals who did not know their date of infection but were diagnosed within 6 months before randomization; and (3) as controls for the MAA, 199 individuals diagnosed with HIV ≥ 2 years before randomization. Participants with low titer and avidity and a baseline viral load > 400 copies/mL were classified as recently infected. A significantly higher percentage of participants who self-reported being infected ≤ 6 months were classified as recently infected compared to participants diagnosed ≥ 2 years (65% [109/167] vs. 2.5% [5/199], p < 0.001). Among the 771 individuals who did not know their duration of infection at randomization, 206 (26.7%) were classified as recently infected. Among those diagnosed with HIV in the 6 months prior to enrollment, the 373 participants who reported recent infection (n = 167) or who had confirmed recent infection by the MAA (n = 206) differed significantly on a number of baseline characteristics from those who had an unknown date of infection and were not confirmed by the MAA (n = 565). Participants recently infected by self-report and/or MAA were younger, more likely to be Asian, less likely to be black, less likely to be heterosexual, more likely to be enrolled at sites in the U.S., Europe or Australia, and have higher HIV RNA levels. There was good agreement between self-report of recency of infection and the MAA. We estimate that 373 participants enrolled in START were infected within 6 months of randomization. Compared to those not recently infected, these participants were younger, had higher HIV RNA levels and were more likely to come from high income countries and from populations such as MSM with more regular HIV testing.

Impact of Allogeneic Hematopoietic Stem Cell Transplantation on the HIV Reservoir and Immune Response in 3 HIV-Infected Individuals.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) can lead to significant changes to the HIV reservoir and HIV immune responses, indicating that further characterization of HIV-infected patients undergoing HSCT is warranted. METHODS: We studied 3 patients who underwent HSCT after either reduced intensity conditioning or myeloablative conditioning regimen. We measured HIV antigens and antibodies (Ag/Ab), HIV-specific CD4 T-cell responses, HIV RNA, and DNA in plasma, peripheral blood mononuclear cells, isolated CD4 T cells from peripheral blood, and lymph node cells. The patients remained on antiretroviral therapy throughout the follow-up period. RESULTS: All patients have been in continued remission for 4-6 years post-HSCT. Analyses of HIV RNA and DNA levels showed substantial reductions in HIV reservoir-related measurements in all 3 patients, changes in immune response varied with pronounced reductions in 2 patients and a less dramatic reduction in 1 patient. One patient experienced unexpected viral rebound 4 years after HSCT. CONCLUSIONS: These 3 cases highlight the substantial changes to the HIV reservoir and the HIV immune response in patients undergoing allogeneic HSCT. The viral rebound observed in 1 patient indicates that replication competent HIV can re-emerge several years after HSCT despite these marked changes.

Managing two decades of visceral leishmaniasis and HIV co-infection: a case report that illustrates the urgent research needs in the field.

Visceral leishmaniasis and HIV co-infection presents diagnostic, monitoring and treatment challenges. This is a report of a co-infected patient who developed multiple complications and treatment side-effects, including renal and liver failure, pancytopenia with recurrent sepsis, along with anal cancer, depression and poor quality-of-life spanning over two decades. Urgent research specific to this cohort is needed.

Reusable venesection tourniquets: a potential source of hospital transmission of multiresistant organisms.

OBJECTIVE: To determine the prevalence of multiresistant organism (MRO) colonisation of reusable venesection tourniquets. DESIGN AND SETTING: A prospective study in a tertiary hospital to collect and analyse reusable venesection tourniquets for the presence of MROs - methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and extended-spectrum ß-lactamase and metallo-ß-lactamase-producing Enterobacteriaceae - using a sensitive enrichment method. Tourniquets were collected and tested during a 10-week period between September and November 2010. MAIN OUTCOME MEASURE: Prevalence of MRO colonisation of tourniquets. RESULTS: The overall colonisation rate of 100 tourniquets randomly collected from general wards, ambulatory care areas and critical care areas was 78%. MROs were isolated from 25 tourniquets collected from a variety of hospital locations, including general wards, the intensive care unit, burns unit and anaesthetic bay. MRSA was isolated from 14 tourniquets and VRE from 19; both MRSA and VRE were isolated from nine tourniquets. There were no microorganisms isolated from 22 tourniquets. CONCLUSION: Reusable tourniquets can be colonised with MROs and may be a potential source of transmission of MROs to hospitalised patients.