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Caroline Wheeler has been reporting on the contaminated blood scandal - the worst treatment disaster in the history of the NHS - for over two decades. She has been integral to the campaign for justice for the victims and their families, and played a pivotal role in persuading Prime Minister Theresa May to agree to the infected blood inquiry in 2019.'Death in the Blood' is based on thousands of government documents, court and inquiry transcripts, plus interviews with prime ministers, cabinet ministers, Downing Street advisers, senior civil servants, doctors, and above all the victims and their families whose personal testimony forms the beating heart of this book.

Achieving functional cure of chronic HBV infection (Hepatitis B surface antigen [HBsAg] clearance, eventually followed by acquisition of anti-hepatitis B surface antigen [Anti-HBs]) in individuals with HIV and HBV infections is a rare event. In this setting, factors related to HBV cure have not yet been fully characterized. HIV-infected individuals with chronic HBV infection enrolled in the French Dat'AIDS cohort (NCT02898987), who started combined antiretroviral (cART)-anti-HBV treatment were retrospectively analyzed for HBsAg loss and Anti-HBs seroconversion. Overall, 1419 naïve-subjects received three different cART-anti-HBV treatment schedule: (1) 3TC or FTC only (n = 150), (2) TDF with or without 3TC or FTC (n = 489) and (3) 3TC or FTC as first line followed by adding/switching to TDF as second line (n = 780). Individuals were followed-up for a median of 89 months (IQR, 56-118). HBV-DNA was < 15 IU/mL in 91% of individuals at the end of the follow-up. Overall, 97 individuals cleared HBsAg (0.7/100 patient-years), of whom, 67 seroconverted for Anti-HBs (0.5/100 patient-years). A high CD4 nadir, a short delay between HBV diagnosis and treatment, a longer time on HBV therapy, an African origin and TDF-based therapy were independent predictors of HBsAg clearance (Probability of odds ratio [OR]>1, >95%) suggested by Bayesian analysis. Also, TDF-based regimen as first line (OR, 3.03) or second line (OR, 2.95) increased rates of HBsAg clearance compared to 3TC or FTC alone, with a 99% probability. HBsAg clearance rate was low in HIV-HBV co-infected cART-anti-HBV treated individuals, but was slightly improved on TDF-based regimen.

We evaluated the prevalence of serum and meningeal cryptococcosis in asymptomatic outpatients with advanced HIV disease (CD4 < 200 cells/mm3) in a cross-sectional screening context in Kinshasa clinics (DRC). Lumbar puncture (LP) was performed in patients with positive serum cryptococcal antigen (CrAg) test, and Cryptococcus spp. isolated from cerebrospinal fluid (CSF) were identified by MALDI-TOF-MS, and characterized using serotyping-PCR, ITS-sequencing and multilocus sequence typing (MLST). The genetic profiles obtained were then compared with those of isolates previously described in symptomatic patients in the same clinics. Forty-seven patients with advanced HIV disease out of 262 included were positive for serum CrAg (18%, 95% CI: 14.2–24.3). The prevalence of asymptomatic cryptococcal meningitis (CM) was then measured at 50% among patients with positive serum CrAg test who consented to LP (19/38). Only four CSF samples were culture positive and all were characterized as Cryptococcus neoformans , molecular type VNI and belonging to two different sequence types (ST): ST93 (3/4) and ST63 (1/4). While ST93 is also the main genomic profile described in advanced HIV disease patients with symptomatic CM in Kinshasa clinics, ST63 has not yet been identified in DRC before. It is likely that future studies involving a large number of strains will be necessary before any definitive conclusions can be drawn on the involved strains in asymptomatic patients.

Background. Our aim was to study the impact of lifelong human immunodeficiency virus (HIV) disease history on the current immune and virological status of perinatally infected patients reaching adulthood. We evaluated blood cell—associated HIV DNA load as an indicator of cell-associated HIV reservoirs and an independent predictor of disease progression. Methods. The ANRS-EP38-IMMIP Study included 93 patients aged 15—24 years who were infected with HIV during the perinatal period. HIV DNA load was quantified by real-time polymerase chain reaction. Results. Eighty-five percent of patients were receiving highly active antiretroviral therapy (HAART), and HIV RNA was undetectable in the plasma of 75% of these patients. The median HIV DNA load was 2.84 (interquartile range, 2.51—3.16) log 10 copies per 10 6 peripheral blood mononuclear cells. In patients with viral suppression, HIV DNA load was independently associated with cumulative HIV RNA viremia over the last 5 years. HIV DNA load was negatively correlated with CD4 cell count in patients with active replication but not in those with undetectable HIV RNA. Conclusions. In perinatally infected youths who are successfully treated, sustained viral suppression is associated with a low HIV DNA load. The absence of association between current HIV DNA load and CD4 cell counts suggests that the unique physiological characteristics of pediatric infection persist after adolescence. Clinical Trials Registration. NCT01055873.

Background Although substantiated by little evidence, concerns about zidovudine-related anaemia in pregnancy have influenced antiretroviral (ARV) regimen choice for preventing mother-to-child transmission of HIV-1, especially in settings where anaemia is common. Methods Eligible HIV-infected pregnant women in Burkina Faso, Kenya and South Africa were followed from 28 weeks of pregnancy until 12–24 months after delivery (n = 1070). Women with a CD4 count of 200-500cells/mm 3 and gestational age 28–36 weeks were randomly assigned to zidovudine-containing triple-ARV prophylaxis continued during breastfeeding up to 6-months, or to zidovudine during pregnancy plus single-dose nevirapine (sd-NVP) at labour. Additionally, two cohorts were established, women with CD4 counts: <200 cells/mm 3 initiated antiretroviral therapy, and >500 cells/mm 3 received zidovudine during pregnancy plus sd-NVP at labour. Mild (haemoglobin 8.0-10.9 g/dl) and severe anaemia (haemoglobin < 8.0 g/dl) occurrence were assessed across study arms, using Kaplan-Meier and multivariable Cox proportional hazards models. Results At enrolment (corresponded to a median 32 weeks gestation), median haemoglobin was 10.3 g/dl (IQR = 9.2-11.1). Severe anaemia occurred subsequently in 194 (18.1%) women, mostly in those with low baseline haemoglobin, lowest socio-economic category, advanced HIV disease, prolonged breastfeeding (≥6 months) and shorter ARV exposure. Severe anaemia incidence was similar in the randomized arms (equivalence P -value = 0.32). After 1–2 months of ARV’s, severe anaemia was significantly reduced in all groups, though remained highest in the low CD4 cohort. Conclusions Severe anaemia occurs at a similar rate in women receiving longer triple zidovudine-containing regimens or shorter prophylaxis. Pregnant women with pre-existing anaemia and advanced HIV disease require close monitoring. Trial registration number ISRCTN71468401

Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy. By examining viral sequences in lymphoid tissue from three HIV-1-infected individuals receiving drug therapy, the authors find phylogenetic evidence for ongoing virus replication, suggesting that the antiretroviral drug concentration in the lymphoid tissue is insufficient to fully suppress the virus; using a mathematical model, they further explain why drug resistance does not necessarily arise as a result. HIV-1 persistence during drug therapy Combinations of antiretroviral drugs can reduce viral replication and reduce viral RNA to undetectable levels in blood in HIV-1 infection, but it is not clear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Steven Wolinsky and colleagues examined viral sequences in lymphoid tissue from three HIV-1 infected individuals receiving drug therapy. They find phylogenetic evidence for ongoing virus replication, suggesting that the antiretroviral drug concentration in the lymphoid tissue is insufficient to fully suppress the virus. They explain using a mathematical model why drug resistance does not necessarily arise under conditions where drug concentrations are insufficient to fully block virus replication.

Quantifying the total-body virus burden in HIV-infected individuals is necessary to understand viral persistence and guide development of cure strategies. Here, Estes et al . find a high burden of residual virus in tissues of SIV-infected monkeys and HIV-infected humans, and evidence of low-level viral replication, even under antiretroviral therapy. In the quest for a functional cure or the eradication of HIV infection, it is necessary to know the sizes of the reservoirs from which infection rebounds after treatment interruption. Thus, we quantified SIV and HIV tissue burdens in tissues of infected nonhuman primates and lymphoid tissue (LT) biopsies from infected humans. Before antiretroviral therapy (ART), LTs contained >98% of the SIV RNA + and DNA + cells. With ART, the numbers of virus (v) RNA+ cells substantially decreased but remained detectable, and their persistence was associated with relatively lower drug concentrations in LT than in peripheral blood. Prolonged ART also decreased the levels of SIV- and HIV-DNA + cells, but the estimated size of the residual tissue burden of 10 8 vDNA + cells potentially containing replication-competent proviruses, along with evidence of continuing virus production in LT despite ART, indicated two important sources for rebound following treatment interruption. The large sizes of these tissue reservoirs underscore challenges in developing 'HIV cure' strategies targeting multiple sources of virus production.

Correspondence to Prof An Hendrix, Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent 9000, Belgium; an.hendrix@ugent.be We read with interest recent papers reporting on the impact of gut microbiota on several aspects of health and disease due to altered intestinal permeability resulting in systemic immune activation by pathogen-associated molecular patterns (PAMP), a process termed microbial translocation.1–4 Common to these studies is the analysis of systemic lipopolysaccharide (LPS), the major outer membrane PAMP of Gram-negative bacteria, to quantitatively assess microbial translocation. Online supplementary table 1 summarises individual patient characteristics; 25 donors asymptomatic of intestinal barrier dysfunction (12 healthy volunteers and 13 patients with cancer during chemotherapy without GI side effects suggestive for intestinal mucositis) and 24 patients with clinically well-defined intestinal barrier dysfunction (13 patients with IBD, 5 patients with cancer with radiation or chemotherapy-induced intestinal mucositis and 6 treatment-naive patients with HIV). [...]LPS-positive bacterial EV are present in plasma, are able to induce immune activation and correlate with impaired barrier integrity in patients diagnosed with IBD, HIV and cancer therapy-induced intestinal mucositis (figure 2).

Florian Klein and colleagues report that treating viremic HIV-1-infected individuals with the broadly neutralizing antibody 10-1074 reduced virus levels in blood, but antibody-resistant virus did emerge. Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log 10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.

Despite receiving antiretroviral therapy, most patients with HIV still have latent reservoirs of the virus; here, these reservoirs are shown to be dominated by viruses with cytotoxic T lymphocyte escape mutations, with potential implications for the development of therapeutic vaccines. HIV-1 reservoirs analysed Antiretroviral therapy does not cure HIV-1 infection: despite drug treatment, most patients still have latent reservoirs of the virus. This study of immune cells isolated from 30 HIV-1-infected patients who had been on antiretroviral therapy for at least two years and had maintained undetectable plasma HIV-1 RNA levels, shows that these viral reservoirs are dominated by viruses with cytotoxic T lymphocyte escape mutations. This finding implies that future directions in therapeutic vaccine design may need to focus on boosting broad cytotoxic T lymphocyte responses. Despite antiretroviral therapy (ART), human immunodeficiency virus (HIV)-1 persists in a stable latent reservoir 1 , 2 , primarily in resting memory CD4 + T cells 3 , 4 . This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed 5 and tested both in vitro and in vivo 6 , 7 , 8 . A key remaining question is whether virus-specific immune mechanisms, including cytotoxic T lymphocytes (CTLs), can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (>98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad-spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.