Julie Fox

Improvement in vitamin D deficiency following antiretroviral regime change: Results from the MONET trial.

Low levels of vitamin D are reported in HIV-infected individuals. In HIV-negative people, low vitamin D levels have been associated with an increased risk of cardiovascular disease and cancer and with worse survival. The MONET trial recruited 256 European patients with HIV RNA <50 copies/ml at screening, while taking either NNRTI- or PI-based HAART. Patients were switched to DRV/r 800/100 mg once daily, either as monotherapy or with two NRTIs. In all, 221 patients were measured for 25-hydroxyvitamin D at a central laboratory before randomized treatment started and at week 96. Multiple regression was used to correlate vitamin D levels with gender, season, ethnic group, treatment group, and use of antiretrovirals. Overall, 80% of patients were male and 91% were white, with a mean age of 44 years. At screening, 170/221 (77%) patients had vitamin D deficiency (<50 nmol/liter). At the screening visit, lower vitamin D levels were significantly associated with calendar month (p = 0.0067), black ethnicity (p = 0.013), use of efavirenz (p = 0.0062), and use of zidovudine (p = 0.015). Mean vitamin D levels were lowest from January to April (mean = 35.8 nmol/liter) and highest in September (mean = 45.4 nmol/liter). Increases in vitamin D between screening and week 96 were significantly greater for patients who discontinued efavirenz or zidovudine before the MONET trial versus those who stopped other antiretrovirals. At screening, lower vitamin D levels were associated with season, race, and use of efavirenz and/or zidovudine. Switching from efavirenz and/or zidovudine to darunavir/ritonavir during the trial led to increases in vitamin D levels. Routine screening of HIV-positive patients for vitamin D should be considered and the optimal management further defined.

Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy: a randomized controlled trial.

CONTEXT Therapies to decrease immune activation might be of benefit in slowing HIV disease progression. OBJECTIVE To determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline. DESIGN, SETTING, AND PATIENTS Randomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/μL. INTERVENTION Hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks. MAIN OUTCOME MEASURES The primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models. RESULTS There was no significant difference in CD8 cell activation between the 2 groups (-4.8% and -4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, -0.6%; 95% CI, -4.8% to 3.6%; P = .80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (-85 cells/μL vs -23 cells/μL at week 48; difference, -62 cells/μL; 95% CI, -115 to -8; P = .03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P = .003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P = .03). CONCLUSION Among HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN30019040.

Sexual transmission of HIV-1.

HIV-1 transmission occurs in a limited number of ways all of which are preventable. Overall, the risk of HIV-1 transmission following a single sexual exposure is low especially in comparison with other sexually transmitted infections (STIs); with estimates of the average probability of male to female HIV-1 transmission only 0.0005-0.0026 per coital act. The risk of acquiring HIV-1 from a single contact varies enormously and is dependant upon the infectiousness of the HIV-1 positive individual and the susceptibility to HIV-1 of their sexual partner. An understanding of the determinants of HIV-1 transmission is important not only to assess the infection risk to an individual when exposed to the virus (e.g. to determine the provision of post exposure prophylaxis), but also to make accurate predictions on the potential spread of HIV-1 infection in a population and to direct appropriate targeted prevention strategies. In this review article we summarise the current literature on the major worldwide source of HIV-1 acquisition, sexual transmission. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

HIV-1–specific CD4+ T lymphocyte turnover and activation increase upon viral rebound

HIV-specific CD4+ T helper lymphocytes are preferred targets for infection. Although complete interruption of combination antiretroviral therapy (ART) can form part of therapeutic manipulations, there is grave concern that the resumption of viral replication might destroy, perhaps irreversibly, these T helper populations. High viremia blocks the proliferation capacity of HIV-specific helper cells. However, cytokine production assays imply that some antigen-specific effector function is retained. Despite this careful work, it remains unclear whether the return of HIV-1 replication physically destroys HIV-1-specific T helper cells in the peripheral blood. Difficulties in producing stable peptide-MHC class II complexes and the very low frequencies of antigen-specific CD4+ T cells have delayed the application of this powerful technique. Here we employ HLA class II tetramers and validate a sensitive, quantitative cell-enrichment technique to detect HIV-1 T helper cells. We studied patients with early-stage HIV infection who were given a short, fixed course of ART as part of a clinical study. We did not find significant deletion of these cells from the peripheral circulation when ART was stopped and unfettered HIV replication returned. The turnover of these virus-specific cells increased and they adopted an effector phenotype when viremia returned.

HLA-associated clinical progression correlates with epitope reversion rates in early human immunodeficiency virus infection.

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) can evade immunity shortly after transmission to a new host but the clinical significance of this early viral adaptation in HIV infection is not clear. We present an analysis of sequence variation from a longitudinal cohort study of HIV adaptation in 189 acute seroconverters followed for up to 3 years. We measured the rates of variation within well-defined epitopes to determine associations with the HLA-linked hazard of disease progression. We found early reversion across both the gag and pol genes, with a 10-fold faster rate of escape in gag (2.2 versus 0.27 forward mutations/1,000 amino acid sites). For most epitopes (23/34), variation in the HLA-matched and HLA-unmatched controls was similar. For a minority of epitopes (8/34, and generally associated with HLA class I alleles that confer clinical benefit), new variants appeared early and consistently over the first 3 years of infection. Reversion occurred early at a rate which was HLA-dependent and correlated with the HLA class 1-associated relative hazard of disease progression and death (P = 0.0008), reinforcing the association between strong cytotoxic T-lymphocyte responses, viral fitness, and disease status. These data provide a comprehensive overview of viral adaptation in the first 3 years of infection. Our findings of HLA-dependent reversion suggest that costs are borne by some escape variants which may benefit the host, a finding contrary to a simple immune evasion paradigm. These epitopes, which are both strongly and frequently recognized, and for which escape involves a high cost to the virus, have the potential to optimize vaccine design.

Longitudinal Study of Influenza Molecular Viral Shedding in Hutterite Communities

BACKGROUND The nature of influenza viral shedding during naturally acquired infection is not well understood. METHODS A cohort study was conducted in Hutterite colonies in Alberta, Canada. Flocked nasal swabs were collected during 3 influenza seasons (2007-2008 to 2009-2010) from both symptomatic and asymptomatic individuals infected with influenza. Samples were tested by real-time reverse-transcription polymerase chain reaction for influenza A and influenza B, and the viral load (VL) was determined for influenza A positive samples. RESULTS Eight hundred thirty-nine participants were included in the cohort; 25% (208) tested positive for influenza viruses. They experienced 238 episodes of viral shedding, of which 23 (10%) were not accompanied by symptoms. For seasonal and pandemic H1N1, VL peaked at or before onset of acute respiratory infection. For H3N2, VL peaked 2 days after the onset of acute respiratory infection, which corresponded to peaks in systemic and respiratory symptom scores. Although the duration of shedding was shorter for asymptomatic participants, the peak level of VL shedding was similar to that of symptomatic participants. Viral loads for children and adults revealed similar patterns. CONCLUSIONS Molecular viral shedding values follow symptom scores, but timing of peak VL varies by subtype. Asymptomatic infections are infrequent.

Low rates of p24 antigen detection using a fourth-generation point of care HIV test

Over one-quarter of people living with HIV infection in the UK are unaware of their HIV infection.1 HIV point-of-care testing (POCT) can greatly improve the uptake and acceptability of HIV testing across hospital and community settings2 3 and, until now, has been carried out using a third-generation antibody assay. As such, cases of suspected PHI are referred for fourth-generation combination testing. Identification of PHI is important, as identification during this hyperinfectiousness period may reduce onward HIV transmission events,4–6 and early intervention with antiretroviral therapy may enhance the long-term clinical outcome.7–10 A significant advance in HIV POCT has been the development of the Determine HIV-1/2 Ag/Ab Combo assay (Inverness Medical, now renamed Alere). This is the first rapid fourth-generation assay for simultaneous detection of HIV p24 antigen and antibodies to HIV-1 and HIV-2. However, this assay has been introduced into routine care in …

Slower CD4 cell decline following cessation of a 3 month course of HAART in primary HIV infection: findings from an observational cohort.

Objective:To investigate the effect of a short course of HAART during primary HIV infection (PHI) on rate of CD4 cell and viral load change. Methods:Data following HAART cessation from 89 individuals (seroconverting 1999–2003) who chose to take a 3 month course of HAART at PHI were compared with 179 untreated controls in CASCADE, using linear and nonlinear random effects models. Participants were non-randomized but frequency matched for age, sex, risk factor, year of seroconversion and presentation within the first 6 months of seroconversion. Time to CD4 cell count < 350 cells/μl and initiation of clinically indicated antiretroviral therapy (ART) were also compared as competing risks. Results:The rate of CD4 cell decline following therapy cessation appeared significantly slower among treated participants than untreated controls: losses of 51 cells/μl [95% confidence interval (CI), 32–69] and 77 cells/μl (95% CI, 65–89), respectively, 3 years after seroconversion (P = 0.011). Based on extrapolated data, viral loads also differed significantly at this point (4.09 and 4.53 copies/ml, respectively). At 2 years, there was no significant difference in mean viral load levels: 4.31 copies/ml (95% CI, 4.14–4.48) and 4.47 copies/ml (95% CI, 4.28–4.66), respectively. CASCADE seroconverters were more likely to reach CD4 cell count < 350 cells/μl or initiate clinically indicated ART (hazard ratio, 1.45; 95% CI, 1.02–2.05; P = 0.039). Conclusion:A short course of ART at PHI may delay CD4 cell decline. Confirmation of this requires a randomized clinical trial powered to address definitively the role of ART intervention in PHI (currently underway through SPARTAC).

Epidemiology of non-B clade forms of HIV-1 in men who have sex with men in the UK.

Objectives:To describe the frequency and risk factors of non-B HIV-1 subtypes in men who have sex with men (MSM) in the UK. Design:Observational study. Methods:MSM diagnosed with HIV-1 infection from 1980–2007, with HIV genotype held in the UK HIV Drug Resistance Database were identified. Protease and reverse transcriptase sequences were collected and viral clade determined using the REGA algorithm. Associations between demographic variables and subtype were analysed using logistic regression. Results:The prevalence of non-B HIV-1 infection amongst MSM in the UK was 5.4% (437/8058). In the UK this increased with year of diagnosis from pre1996 to 2002, and has subsequently remained relatively stable at around 7–9% after 2002, with a recent increase in 2007 to 13%. Multivariate analysis showed that acquisition of non-B HIV-1 infection was independently associated with later year of HIV diagnosis (P < 0.001), black ethnicity (P < 0.001) and non-European country of birth (P = 0.01). Age was also associated with subtype with individuals aged 25–39 years being less likely to have non-B virus than those aged less than 25 years (P = 0.01). Restricting the analysis to white men born in the UK, the association between subtype and year of diagnosis remained statistically significant (P < 0.001), as did the association with age (P < 0.001). Discussion:The number of MSM in the UK infected with non-B clade HIV-1 is increasing, suggesting that the sociodemographic boundaries between HIV-1 viral subtypes globally are diminishing. Should viral subtypes be relevant to clinical disease progression or vaccine design, the changing pattern of distribution will need to be taken into account.

Primary HIV infection: to treat or not to treat?

Purpose of review The aim of this article is to review new data on the use of antiretroviral therapy in primary HIV infection. Recent findings The concept of ‘hit HIV hard and early’ supporting the use of antiretroviral therapy to treat the early stages of HIV infection has been revisited. Recent demonstration of massive, rapid and largely irreversible HIV-mediated destruction of memory CD4+ T cells predominantly occurring in the gut suggests that primary HIV infection may be the only time that intervention could confer lasting immunological benefit. There are no data, however, from randomized controlled trials supporting the use of antiretroviral therapy in primary HIV infection, although a number of observational studies have demonstrated limited, transient improvements in measured immunological outcomes. The first randomized controlled trials powered to address whether antiretroviral therapy of a limited duration in primary HIV infection can influence long-term CD4 decline (SPARTAC) is now fully recruited but will report in 2–3 years. In addition, given that individuals with primary HIV infection contribute disproportionately towards onward HIV transmission, there may be an additional public health impetus for earlier diagnosis and intervention in primary HIV infection. Summary In the absence of randomized controlled trials data demonstrating clinical benefit of antiretroviral therapy intervention in primary HIV infection, clinical guidelines remain unclear. Intervention seems a logical strategy to counter the high viraemia, enhanced onward transmissibility, and immunological destruction which occurs during primary HIV infection. The nature, duration and timing of that intervention after HIV acquisition remains unknown.