Bacille Calmette-Guérin vaccine-related disease in HIV-infected children: a systematic review

Objective: To describe the characteristics and risk of bacille Calmette-Guérin (BCG) vaccine related disease in human immunodeficiency virus (HIV) infected infants.
Methods: Systematic literature review of articles published from 1950 to April 2009 in the English language. We identified all microbiologically confirmed cases of disseminated BCG disease in vertically HIV-infected children reported in the literature.
Results: Sixteen observational studies and 11 case reports/series were included. Observational studies suffered from high rates of loss to follow-up and death. Loco-regional BCG disease was reported in both HIV-infected and non-infected children. Disseminated BCG disease was reported only in children with immunodeficiency and only in studies employing sophisticated laboratory techniques. Sixty-nine cases of disseminated BCG were identified in the literature: 47 cases were reported in six observational studies, the majority (41/47) from the Western Cape of South Africa. A Brazilian cohort study reported no cases of disseminated BCG amongst 66 HIV-infected children observed over a 7-year period. A recent South African surveillance study reported 32 cases of disseminated BCG over a 3-year period, estimating the risk of disseminated BCG to be 992 per 100 000 vaccinations in HIV-infected children. Few cases of severe disseminated TB were reported in the cohort studies among HIV-infected children vaccinated with BCG.
Conclusion: Data on the risk of BCG vaccination in HIV-infected children are limited. Targeted surveillance for BCG complications employing sophisticated diagnostic techniques is required to inform vaccination policy.

Renal and gastrointestinal amyloidosis in an HIV-infected injection drug user

A 30-year-old HIV-infected intravenous drug user presented with sepsis, acute renal failure, oedema, proteinuria and iron deficiency anaemia. After extensive investigation, a diagnosis of reactive systemic AA (amyloid, serum amyloid A protein) amyloidosis was made on the basis of renal, gastric and duodenal biopsies.

Analysis of serious non-AIDS events among HIV-infected adults at Latin American sites

Acquired immune deficiency appears to be associated with serious non-AIDS (SNA)-defining conditions such as cardiovascular disease, liver and renal insufficiency and non-AIDS-related malignancies. We analysed the incidence of, and factors associated with, several SNA events in the LATINA retrospective cohort.

Medication compliance and satisfaction with treatment for HIV disease in a sample of African-American crack cocaine smokers

The development of treatment regimes for African-American HIV-infected crack cocaine users has often been based on assumptions about compliance with medication regimes rather than evidence. This study sought to obtain baseline information on the adherence to antiretroviral medications by members of this important risk population in Houston, Texas. It was found that for only 5 of a range of 16 antiviral medications was there a significant correlation between levels of compliance reported by respondents and their beliefs as to how effective these medications are. Medication compliance was also found not to be associated with frequency of crack cocaine use in the month prior to interview. Furthermore, irrespective of both gender and their reported extent of medication compliance, the respondents tended to report positive relationships with their treating physician, with higher levels of satisfaction reported by women. These results suggest that the majority of African-American crack cocaine users are able to comply with HIV treatment regimes, with more than half (53%) claiming full compliance for one or more medications, and a further one third (31%) claiming compliance more than half the time. Moreover, these findings suggest that they will continue to take antiretroviral medications even if they have doubts about the effectiveness of these medications.

Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1

Manifestations of viral infections can differ between women and men, and marked sex differences have been described in the course of HIV-1 disease. HIV-1-infected women tend to have lower viral loads early in HIV-1 infection but progress faster to AIDS for a given viral load than men. Here we show substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce markedly more interferon-alpha (IFN-alpha) in response to HIV-1-encoded Toll-like receptor 7 (TLR7) ligands than pDCs derived from men, resulting in stronger secondary activation of CD8(+) T cells. In line with these in vitro studies, treatment-naive women chronically infected with HIV-1 had considerably higher levels of CD8(+) T cell activation than men after adjusting for viral load. These data show that sex differences in TLR-mediated activation of pDCs may account for higher immune activation in women compared to men at a given HIV-1 viral load and provide a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women compared to men. Modulation of the TLR7 pathway in pDCs may therefore represent a new approach to reduce HIV-1-associated pathology.

Complementary medicine use among people living with HIV/AIDS in Victoria, Australia: practices, attitudes and perceptions

There is limited evidence suggesting the underlying reasons for the use of complementary and alternative medicines (CAMs) by people with HIV/AIDS, or individual attitudes and beliefs about the use of CAMs. Using focus groups and a survey with 151 individuals attending the HIV Clinics at The Alfred Hospital, Melbourne, we aimed to provide insights into factors that influence the use of CAMs among people living with HIV/AIDS. Roughly half (49%) of the participants had used CAMs to manage their HIV/AIDs. Users of CAMs utilized a wide range of treatments in managing their condition, but costs of the CAMs meant that users were not necessarily able to use them as much as they might have liked. Use of CAMs was based on a desire to find something beneficial rather than on being dissatisfied with conventional medicine. Further research is needed into (a) the effects of CAMs and (b) the enhancement of communication and collaboration between patients, doctors and complementary medicine practitioners.

"I will start treatment when I think the time is right":HIV-positive gay men talk about their decision not to access antiretroviral therapy.

In a qualitative study, 20 HIV-infected Australian gay men were interviewed about their decision not to access antiretroviral drug therapy. The main reasons given for the decision were fear of side effects; fear of long-term damage to body organs; the inconvenience of the treatment regimens; belief that the regimen's demands would be a threat to morale; and belief that there was no reason to start therapy in the absence of AIDS-related symptoms. Actions taken by the men to monitor and maintain their health included seeing a doctor regularly; having regular T-cell and viral load tests; and trying to maintain a positive outlook by not letting HIV/AIDS 'take over' their lives. Almost half the men considered they had been subjected to unreasonable pressure to access therapy and there was considerable pride at having resisted this pressure. The findings suggest that the men disagreed with the biomedical model for managing HIV/AIDS only on the question of if and when to access therapy. They also suggest that underlying the men's dissent from the biomedical model was a different mode of thinking than is required by the model: while the model demands thinking that is abstract, the men focused strongly on factors close to the 'here and now' of immediate experience. The practical implications of the findings are explored.

Gay men's estimates of the likelihood of HIV transmission in sexual behaviours

In 3 studies we recorded gay men's estimates of the likelihood that HIV would be transmitted in various sexual behaviours. In Study 1 (data collected 1993, n=92), the men were found to believe that transmissibility is very much greater than it actually is; that insertive unprotected anal intercourse (UAI) by an HIV-infected partner is made safer by withdrawal before ejaculation, and very much safer by withdrawal before either ejaculation or pre-ejaculation; that UAI is very much safer when an infected partner is receptive rather than insertive; that insertive oral sex by an infected partner is much less risky than even the safest variant of UAI; that HIV is less transmissible very early after infection than later on; and that risk accumulates over repeated acts of UAI less than it actually does. In Study 2 (data collected 1997/8, n=200), it was found that younger and older uninfected men generally gave similar estimates of transmissibility, but that infected men gave somewhat lower estimates than uninfected men; and that estimates were unaffected by asking the men to imagine that they themselves, rather than a hypothetical other gay man, were engaging in the behaviours. Comparison of the 1993 and 1997/8 results suggested that there had been some effect of an educational campaign warning of the dangers of withdrawal; however, there had been no effect either of a campaign warning of the dangers of receptive UAI by an infected partner, or of publicity given to the greater transmissibility of HIV shortly after infection. In Study 3 (data collected 1999, n=59), men induced into a positive mood were found to give lower estimates of transmissibility than either men induced into a neutral mood or men induced into a negative mood. It is argued that the results reveal the important contribution made to gay men's transmissibility estimates by cognitive strategies (such as the 'availability heuristic' and 'anchoring and adjustment') known to be general characteristics of human information-processing. Implications of the findings for AIDS education are discussed.

Reconstructing the incidence of human immunodeficiency virus (HIV) in Hong Kong by using data from HIV positive tests and diagnoses of acquired immune deficiency syndrome

The human immunodeficiency virus–acquired immune deficiency syndrome (HIV–AIDS) epidemic in Hong Kong has been under surveillance in the form of voluntary reporting since 1984. However, there has been little discussion or research on the reconstruction of the HIV incidence curve. This paper is the first to use a modified back-projection method to estimate the incidence of HIV in Hong Kong on the basis of the number of positive HIV tests only. The model proposed has several advantages over the original back-projection method based on AIDS data only. First, not all HIV-infected individuals will develop AIDS by the time of analysis, but some of them may undertake an HIV test; therefore, the HIV data set contains more information than the AIDS data set. Second, the HIV diagnosis curve usually has a smoother pattern than the AIDS diagnosis curve, as it is not affected by redefinition of AIDS. Third, the time to positive HIV diagnosis is unlikely to be affected by treatment effects, as it is unlikely that an individual receives medication before the diagnosis of HIV. Fourth, the induction period from HIV infection to the first HIV positive test is usually shorter than the incubation period which is from HIV infection to diagnosis of AIDS. With a shorter induction period, more information becomes available for estimating the HIV incidence curve. Finally, this method requires the number of positive HIV diagnoses only, which is readily available from HIV–AIDS surveillance systems in many countries. It is estimated that, in Hong Kong, the cumulative number of HIV infections during the period 1979–2000 is about 2600, whereas an estimate based only on AIDS data seems to give an underestimate.

X4 and R5 HIV-1 have distinct post-entry requirements for uracil DNA glycosylase during infection of primary cells

It has been assumed that R5 and X4 HIV utilize similar strategies to support viral cDNA synthesis post viral entry. In this study, we provide evidence to show that R5 and X4 HIV have distinct requirements for host cell uracil DNA glycosylase (UNG2) during the early stage of infection. UNG2 has been previously implicated in HIV infection, but its precise role remains controversial. In this study we show that, although UNG2 is highly expressed in different cell lines, UNG2 levels are low in the natural host cells of HIV. Short interfering RNA knockdown of endogenous UNG2 in primary cells showed that UNG2 is required for R5 but not X4 HIV infection and that this requirement is bypassed when HIV enters the target cell via vesicular stomatitis virus envelope-glycoprotein-mediated endocytosis. We also show that short interfering RNA knockdown of UNG2 in virus-producing primary cells leads to defective R5 HIV virions that are unable to complete viral cDNA synthesis. Quantitative PCR analysis revealed that endogenous UNG2 levels are transiently up-regulated post HIV infection, and this increase in UNG2 mRNA is ∼10–20 times higher in R5 versus X4 HIV-infected cells. Our data show that both virion-associated UNG2 and HIV infection-induced UNG2 expression are critical for reverse transcription during R5 but not X4 HIV infection. More importantly, we have made the novel observation that R5 and X4 HIV have distinct host cell factor requirements and differential capacities to induce gene expression during the early stages of infection. These differences may result from activation of distinct signaling cascades and/or infection of divergent T-lymphocyte subpopulations.

HIV-1 down-modulates γ signaling chain of FcγR in human macrophages : a possible mechanism for inhibition of phagocytosis

HIV-1 infection impairs a number of macrophage effector functions, thereby contributing to development of opportunistic infections and the pathogenesis of AIDS. FcγR-mediated phagocytosis by human monocyte-derived macrophages (MDM) is inhibited by HIV-1 infection in vitro, and the underlying mechanism was investigated in this study. Inhibition of phagocytosis directly correlated with the multiplicity of HIV-1 infection. Expression of surface FcγRs was unaffected by HIV-1 infection, suggesting that inhibition of phagocytosis occurred during or after receptor binding. HIV-1 infection of MDM markedly inhibited tyrosine phosphorylation of the cellular proteins, which occurs following engagement of FcγRs, suggesting a defect downstream of initial receptor activation. FcγR-mediated phagocytosis in HIV-infected MDM was associated with inhibition of phosphorylation of tyrosine kinases from two different families, Hck and Syk, defective formation of Syk complexes with other tyrosine-phosphorylated proteins, and inhibition of paxillin activation. Down-modulation of protein expression but not mRNA of the γ signaling subunit of FcγR (a docking site for Syk) was observed in HIV-infected MDM. Infection of MDM with a construct of HIV-1 in which nef was replaced with the gene for the γ signaling subunit augmented FcγR-mediated phagocytosis, suggesting that down-modulation of γ-chain protein expression in HIV-infected MDM caused the defective FcγR-mediated signaling and impairment of phagocytosis. This study is the first to demonstrate a specific alteration in phagocytosis signal transduction pathway, which provides a mechanism for the observed impaired FcγR-mediated phagocytosis in HIV-infected macrophages and contributes to the understanding of how HIV-1 impairs cell-mediated immunity leading to HIV-1 disease progression.

Intracellular dynamics of HIV infection

Early studies of HIV infection dynamics suggested that virus-producing HIV-infected cells had an average half-life of approximately 1 day. However, whether this average behavior is reflective of the dynamics of individual infected cells is unclear. Here, we use HIV-enhanced green fluorescent protein (EGFP) constructs and flow cytometry sorting to explore the dynamics of cell infection, viral protein production, and cell death in vitro. By following the numbers of productively infected cells expressing EGFP over time, we show that infected cell death slows down over time. Although infected cell death in vivo could be very different, our results suggest that the constant decay of cell numbers observed in vivo during antiretroviral treatment could reflect a balance of cell death and delayed viral protein production. We observe no correlation between viral protein production and death rate of productively infected cells, showing that viral protein production is not likely to be the sole determinant of the death of HIV-infected cells. Finally, we show that all observed features can be reproduced by a simple model in which infected cells have broad distributions of productive life spans, times to start viral protein production, and viral protein production rates. This broad spectrum of the level and timing of viral protein production provides new insights into the behavior and characteristics of HIV-infected cells.

The effects of mood states on the AIDS-related judgements of gay men

In two studies, the effects of induced mood on the AIDS-related judgements of gay men were investigated. Participants were induced into a positive, neutral, or negative mood by recall of affect-laden autobiographical memories; they then made AIDS-related judgements. In Study 1 (n=30), the men indicated their level of agreement with statements expressing optimism about the efficacy of antiretroviral treatments for HIV/AIDS. Those induced into a positive mood indicated stronger agreement than did those induced into a neutral or negative mood. In Study 2 (n=83), participants read brief descriptions of men they did not know and estimated the likelihood that they were HIV-infected. Each sketch highlighted one characteristic of the man described. There were two versions of each sketch (e.g., the versions of the sketch highlighting intelligence described the man either as very intelligent or as very unintelligent), given to different participants. Stereotype use was inferred if significantly different estimates were given for the two versions of a sketch. Reliance on stereotypes was found most often in the positive mood condition and least often in the negative mood condition. The findings are consistent with, and suggest explanations for, earlier correlational evidence that, in gay men of the age group studied, sexual risk-taking is associated with a positive mood. Suggestions are made for how AIDS educators might address the contributions of mood states to sexual risk-taking.

Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6

CYP2B6 is mainly expressed in the liver that has been thought historically to play an insignificant role in human drug metabolism. However, increased interest in this enzyme has been stimulated by the discovery of polymorphic and ethnic differences in CYP2B6 expression, identification of additional substrates for CYP2B6, and evidence for co-regulation with CYP3A4. This paper updates our knowledge about the structure, function, regulation and polymorphism of CYP2B6. CYP2B6 can metabolise approximately 8% of clinically used drugs (n > 60), including cyclophosphamide, ifosfamide, tamoxifen, ketamine, artemisinin, nevirapine, efavirenz, bupropion, sibutramine, and propofol. CYP2B6 is one of the CYP enzymes that bioactivate several procarcinogens and toxicants. This enzyme also metabolizes arachidonic acid, lauric acid, 17beta-estradiol, estrone, ethinylestradiol, and testosterone. Typical substrates of CYP2B6 are non-planar molecules, neutral or weakly basic, highly lipophilic with one or two hydrogen-bond acceptors. The crystal structure of CYP2B6 has not been resolved, while several pharmacophore and homology models of human CYP2B6 have been reported. Human CYP2B6 is closely regulated by constitutive androstane receptor (CAR/NR1I3) which can activate CYP2B6 expression upon ligand binding. Pregnane X receptor and glucocorticoid receptor also play a role in the regulation of CYP2B6. Induction of CYP2B6 may partially explain some clinical drug interactions observed. For example, coadministered carbamazepine decreases the systemic exposure of bupropion. There is a wide interindividual variability in the expression and activity of CYP2B6. Such a large variability is probably due to effects of genetic polymorphisms and exposure to drugs that are inducers or inhibitors of CYP2B6. To date, at least 28 allelic variants and some subvariants of CYP2B6 (*1B through *29) have been described and some of them have been shown to have important functional impact on drug clearance and drug response. For example, the efavirenz plasma levels in African-American subjects with the CYP2B6 homozygous 516T/T genotype are approximately 3-fold higher than individuals carrying the homozygous G/G genotype. The CYP2B6 516T/T genotype is associated with 1.7-fold greater plasma levels of nevirapine in HIV-infected patients. Smokers with the 1459C>T (R487C) variant of CYP2B6 may be more vulnerable to abstinence symptoms and relapse following treatment with bupropion as a smoking cessation agent. Further studies in the structure, function, regulation and polymorphism of CYP2B6 are warranted.

Global, regional, and national levels and causes of maternal mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013

BACKGROUND: The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100,000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery. METHODS: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values. FINDINGS: 292,982 (95% UI 261,017-327,792) maternal deaths occurred in 2013, compared with 376,034 (343,483-407,574) in 1990. The global annual rate of change in the MMR was -0·3% (-1·1 to 0·6) from 1990 to 2003, and -2·7% (-3·9 to -1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0·4% (0·2-0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1-1262·8) in South Sudan to 2·4 (1·6-3·6) in Iceland. INTERPRETATION: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa. FUNDING: Bill & Melinda Gates Foundation.