Rebecca F. Baggaley

Pandemic Potential of a Strain of Influenza A (H1N1): Early Findings

Swine Flu Benchmark The World Health Organization (WHO) announced on 29 April 2009, a level-5 pandemic alert for a strain of H1N1 influenza originating in pigs in Mexico and transmitting from human to human in several countries. Fraser et al. (p. 1557, published online 11 May; see the cover) amassed a team of experts in Mexico and WHO to make an initial assessment of the outbreak with a view to guiding future policy. The outbreak appears to have originated in mid-February in the village of La Gloria, Veracruz, where over half the population suffered acute respiratory illness, affecting more than 61% of children under 15 years old in the community. The basic reproduction number (the number of people infected per patient) is in the range of 1.5—similar or less than that of the pandemics of 1918, 1957, and 1968. There remain significant uncertainties about the severity of this outbreak, which makes it difficult to compare the economic and societal costs of intervention with lives saved and the risks of generating antiviral resistance. An international collaborative effort has analyzed the initial dynamics of the swine flu outbreak. A novel influenza A (H1N1) virus has spread rapidly across the globe. Judging its pandemic potential is difficult with limited data, but nevertheless essential to inform appropriate health responses. By analyzing the outbreak in Mexico, early data on international spread, and viral genetic diversity, we make an early assessment of transmissibility and severity. Our estimates suggest that 23,000 (range 6000 to 32,000) individuals had been infected in Mexico by late April, giving an estimated case fatality ratio (CFR) of 0.4% (range: 0.3 to 1.8%) based on confirmed and suspected deaths reported to that time. In a community outbreak in the small community of La Gloria, Veracruz, no deaths were attributed to infection, giving an upper 95% bound on CFR of 0.6%. Thus, although substantial uncertainty remains, clinical severity appears less than that seen in the 1918 influenza pandemic but comparable with that seen in the 1957 pandemic. Clinical attack rates in children in La Gloria were twice that in adults (<15 years of age: 61%; ≥15 years: 29%). Three different epidemiological analyses gave basic reproduction number (R0) estimates in the range of 1.4 to 1.6, whereas a genetic analysis gave a central estimate of 1.2. This range of values is consistent with 14 to 73 generations of human-to-human transmission having occurred in Mexico to late April. Transmissibility is therefore substantially higher than that of seasonal flu, and comparable with lower estimates of R0 obtained from previous influenza pandemics.

Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies

We did a systematic review and meta-analysis of observational studies of the risk of HIV-1 transmission per heterosexual contact. 43 publications comprising 25 different study populations were identified. Pooled female-to-male (0.04% per act [95% CI 0.01-0.14]) and male-to-female (0.08% per act [95% CI 0.06-0.11]) transmission estimates in high-income countries indicated a low risk of infection in the absence of antiretrovirals. Low-income country female-to-male (0.38% per act [95% CI 0.13-1.10]) and male-to-female (0.30% per act [95% CI 0.14-0.63]) estimates in the absence of commercial sex exposure (CSE) were higher. In meta-regression analysis, the infectivity across estimates in the absence of CSE was significantly associated with sex, setting, the interaction between setting and sex, and antenatal HIV prevalence. The pooled receptive anal intercourse estimate was much higher (1.7% per act [95% CI 0.3-8.9]). Estimates for the early and late phases of HIV infection were 9.2 (95% CI 4.5-18.8) and 7.3 (95% CI 4.5-11.9) times larger, respectively, than for the asymptomatic phase. After adjusting for CSE, presence or history of genital ulcers in either couple member increased per-act infectivity 5.3 (95% CI 1.4-19.5) times versus no sexually transmitted infection. Study estimates among non-circumcised men were at least twice those among circumcised men. Low-income country estimates were more heterogeneous than high-income country estimates, which indicates poorer study quality, greater heterogeneity of risk factors, or under-reporting of high-risk behaviour. Efforts are needed to better understand these differences and to quantify infectivity in low-income countries.

HIV transmission risk through anal intercourse: systematic review, meta-analysis and implications for HIV prevention

Background The human immunodeficiency virus (HIV) infectiousness of anal intercourse (AI) has not been systematically reviewed, despite its role driving HIV epidemics among men who have sex with men (MSM) and its potential contribution to heterosexual spread. We assessed the per-act and per-partner HIV transmission risk from AI exposure for heterosexuals and MSM and its implications for HIV prevention. Methods Systematic review and meta-analysis of the literature on HIV-1 infectiousness through AI was conducted. PubMed was searched to September 2008. A binomial model explored the individual risk of HIV infection with and without highly active antiretroviral therapy (HAART). Results A total of 62 643 titles were searched; four publications reporting per-act and 12 reporting per-partner transmission estimates were included. Overall, random effects model summary estimates were 1.4% [95% confidence interval (CI) 0.2–2.5)] and 40.4% (95% CI 6.0–74.9) for per-act and per-partner unprotected receptive AI (URAI), respectively. There was no significant difference between per-act risks of URAI for heterosexuals and MSM. Per-partner unprotected insertive AI (UIAI) and combined URAI–UIAI risk were 21.7% (95% CI 0.2–43.3) and 39.9% (95% CI 22.5–57.4), respectively, with no available per-act estimates. Per-partner combined URAI–UIAI summary estimates, which adjusted for additional exposures other than AI with a ‘main’ partner [7.9% (95% CI 1.2–14.5)], were lower than crude (unadjusted) estimates [48.1% (95% CI 35.3–60.8)]. Our modelling demonstrated that it would require unreasonably low numbers of AI HIV exposures per partnership to reconcile the summary per-act and per-partner estimates, suggesting considerable variability in AI infectiousness between and within partnerships over time. AI may substantially increase HIV transmission risk even if the infected partner is receiving HAART; however, predictions are highly sensitive to infectiousness assumptions based on viral load. Conclusions Unprotected AI is a high-risk practice for HIV transmission, probably with substantial variation in infectiousness. The significant heterogeneity between infectiousness estimates means that pooled AI HIV transmission probabilities should be used with caution. Recent reported rises in AI among heterosexuals suggest a greater understanding of the role AI plays in heterosexual sex lives may be increasingly important for HIV prevention.

Modelling the Impact of Antiretroviral Use in Resource-Poor Settings

Background The anticipated scale-up of antiretroviral therapy (ART) in high-prevalence, resource-constrained settings requires operational research to guide policy on the design of treatment programmes. Mathematical models can explore the potential impacts of various treatment strategies, including timing of treatment initiation and provision of laboratory monitoring facilities, to complement evidence from pilot programmes. Methods and Findings A deterministic model of HIV transmission incorporating ART and stratifying infection progression into stages was constructed. The impact of ART was evaluated for various scenarios and treatment strategies, with different levels of coverage, patient eligibility, and other parameter values. These strategies included the provision of laboratory facilities that perform CD4 counts and viral load testing, and the timing of the stage of infection at which treatment is initiated. In our analysis, unlimited ART provision initiated at late-stage infection (AIDS) increased prevalence of HIV infection. The effect of additionally treating pre-AIDS patients depended on the behaviour change of treated patients. Different coverage levels for ART do not affect benefits such as life-years gained per person-year of treatment and have minimal effect on infections averted when treating AIDS patients only. Scaling up treatment of pre-AIDS patients resulted in more infections being averted per person-year of treatment, but the absolute number of infections averted remained small. As coverage increased in the models, the emergence and risk of spread of drug resistance increased. Withdrawal of failing treatment (clinical resurgence of symptoms), immunologic (CD4 count decline), or virologic failure (viral rebound) increased the number of infected individuals who could benefit from ART, but effectiveness per person is compromised. Only withdrawal at a very early stage of treatment failure, soon after viral rebound, would have a substantial impact on emergence of drug resistance. Conclusions Our analysis found that ART cannot be seen as a direct transmission prevention measure, regardless of the degree of coverage. Counselling of patients to promote safe sexual practices is essential and must aim to effect long-term change. The chief aims of an ART programme, such as maximised number of patients treated or optimised treatment per patient, will determine which treatment strategy is most effective.

Risk of HIV-1 transmission for parenteral exposure and blood transfusion : a systematic review and meta-analysis

Background:The role of iatrogenic transmission within the HIV/AIDS pandemic remains contentious. Estimates of the risk of HIV transmission from injections and blood transfusions are required to inform appropriate prevention policy. Objectives:Systematic review and meta-analysis of the literature on HIV-1 infectivity for parenteral transmission and blood transfusion. Review methods:All identified studies with relevant transmission probability estimates up to May 2005 were included. Statistical methods:When appropriate, summary estimates for accidental percutaneous and blood product exposures were derived. Results:Infectivity estimates following a needlestick exposure ranged from 0.00 to 2.38% [weighted mean, 0.23%; 95% confidence interval (CI), 0.00–0.46%; n = 21]. Three estimates of infectivity per intravenous drug injection ranged from 0.63 to 2.4% (median, 0.8%); a summary estimate could not be calculated. The quality of the only estimate of infectivity per contaminated medical injection (1.9–6.9%) was assessed. Instead we propose a range of 0.24–0.65%. Infectivity estimates for confirmed contaminated blood transfusions range from 88.3 to 100.0% (weighted mean, 92.5%; 95% CI, 89.0–96.1%; n = 6). Conclusions:Infectivity estimates for infected blood transfusions are larger than for other modes of HIV transmission. Few studies on transmission risk per contaminated injection were found. However, transmission risk per needlestick injury, where needles are more likely to be rinsed or disinfected between recipients (especially for medical injections), may be representative of non-intravenous medical injections and lower than the risk from intravenous injections, which are likely to be deeper and to involve more fluids. Further work is needed to better estimate transmission probability related to contaminated injections and its likely contribution to overall HIV transmission.

Health of women after severe obstetric complications in Burkina Faso: a longitudinal study

BACKGROUND Little is known about the health of women who survive obstetric complications in poor countries. Our aim was to determine how severe obstetric complications in Burkina Faso affect a range of health, social, and economic indicators in the first year post partum. METHODS We did a prospective cohort study of women with severe obstetric complications recruited in hospitals when their pregnancy ended with a livebirth (n=199), perinatal death (74), or a lost pregnancy (64). For every woman with severe obstetric complications, two unmatched control women with uncomplicated delivery were sampled in the same hospital (677). All women were followed up for 1 year. FINDINGS Women with severe obstetric complications were poorer and less educated at baseline than were women with uncomplicated delivery. Women with severe obstetric complications, and their babies, were significantly more likely to die after discharge: six (2%) of the 337 women with severe obstetric complications died within 1 year, compared with none of the women with uncomplicated delivery (unadjusted p=0.001); 17 babies of women with severe obstetric complications died within 1 year, compared with 18 of those born by uncomplicated delivery (hazard ratio for mortality 4.67, 95% CI 1.68-13.04, adjusted for loss to follow-up and confounders; p=0.003). Women with severe obstetric complications were significantly more likely to have experienced depression and anxiety at 3 months (odds ratio 1.82, 95% CI 1.18-2.80), to have experienced suicidal thoughts within the past year at all time points (2.27, 1.33-3.89 at 3 months; 2.30, 1.17-4.50 at 6 months; 2.26, 1.30-3.95 at 12 months), and to report the pregnancy having had a negative effect on their lives at all time points (1.54, 1.04-2.30 at 3 months; 2.30, 1.56-3.39 at 6 months; 2.44, 1.63-3.65 at 12 months) than were women with uncomplicated delivery. INTERPRETATION Women who give birth with severe obstetric complications are at greater risk of death and mental-health problems than are women with uncomplicated delivery. Greater resources are needed to ensure that these women receive adequate care before and after discharge from hospital.

The epidemiological impact of antiretroviral use predicted by mathematical models: a review

This review summarises theoretical studies attempting to assess the population impact of antiretroviral therapy (ART) use on mortality and HIV incidence. We describe the key parameters that determine the impact of therapy, and argue that mathematical models of disease transmission are the natural framework within which to explore the interaction between antiviral use and the dynamics of an HIV epidemic. Our review focuses on the potential effects of ART in resource-poor settings. We discuss choice of model type and structure, the potential for risk behaviour change following widespread introduction of ART, the importance of the stage of HIV infection at which treatment is initiated, and the potential for spread of drug resistance. These issues are illustrated with results from models of HIV transmission. We demonstrate that HIV transmission models predicting the impact of ART use should incorporate a realistic progression through stages of HIV infection in order to capture the effect of the timing of treatment initiation on disease spread. The realism of existing models falls short of properly reproducing patterns of diagnosis timing, incorporating heterogeneity in sexual behaviour, and describing the evolution and transmission of drug resistance. The uncertainty surrounding certain effects of ART, such as changes in sexual behaviour and transmission of ART-resistant HIV strains, demands exploration of best and worst case scenarios in modelling, but this must be complemented by surveillance and behavioural surveys to quantify such effects in settings where ART is implemented.

Modelling HIV epidemics in the antiretroviral era: the UNAIDS Estimation and Projection package 2009

Objective The UNAIDS Estimation and Projection Package (EPP) is a tool for country-level estimation and short-term projection of HIV/AIDS epidemics based on fitting observed HIV surveillance data on prevalence. This paper describes the adaptations made in EPP 2009, the latest version of this tool, as new issues have arisen in the global response, in particular the global expansion of antiretroviral therapy (ART). Results By December 2008 over 4 million people globally were receiving ART, substantially improving their survival. EPP 2009 required modifications to correctly adjust for the effects of ART on incidence and the resulting increases in HIV prevalence in populations with high ART coverage. Because changing incidence is a better indicator of program impact, the 2009 series of UNAIDS tools also focuses on calculating incidence alongside prevalence. Other changes made in EPP 2009 include: an improved procedure, incremental mixture importance sampling, for efficiently generating more accurate uncertainty estimates; provisions to vary the urban/rural population ratios in generalised epidemics over time; introduction of a modified epidemic model that accommodates behaviour change in low incidence settings; and improved procedures for calibrating models. This paper describes these changes in detail, and discusses anticipated future changes in the next version of EPP.

Systematic review of orogenital HIV-1 transmission probabilities

Background The objective was to assess the risk of HIV transmission from orogenital intercourse (OI). Methods Systematic review of the literature on HIV-1 infectiousness through OI conducted according to MOOSE guidelines for reviews of observational studies. The PubMed database and bibliographies of relevant articles were searched to July 2007. Results Of the titles, 56 214 were searched from which 10 potentially appropriate studies were identified; two additional studies were identified through bibliographies and one through discussion with experts. There were 10 included studies, providing estimates of transmission probabilities per-partner (n = 5), incidence per-partner (n = 3), per-study participant (n = 3, following initially seronegative individuals whose partners are of unknown serostatus) and per-act (n = 3). Only four of 10 studies reported non-zero estimates: two per-partner estimates (20%, 95% CI: 6–51, n = 10 and a model-based estimate, 1%, range 0.85–2.3%), one per-study participant estimate (0.37%, 95% CI: 0.10–1.34%) and one per-act estimate (0.04%, 95% CI: 0.01–0.17%). Upper bounds for the 95% CI for zero estimates tended to be relatively large due to the small study sample sizes: 9.0, 12.1 and 2.8% for per-partner; 4.7, 9.6 and 1.8 per 100 person-years for incidence per-partner; 4.4% per-study participant and 0.45 and 0.02% for per-act. Given the small number of studies, a meta-analysis was not considered appropriate. Conclusions There are currently insufficient data to estimate precisely the risk from OI exposure. The low risk of transmission evident from identified studies means that more and larger studies would be required to provide sufficient evidence to derive more precise estimates.

Detecting depression after pregnancy: the validity of the K10 and K6 in Burkina Faso.

Objective  The K10 and K6 are short rating scales designed to detect individuals at risk for depressive disorder, with or without anxiety. Despite being widely used, they have not yet been validated for detecting postnatal depression. We describe the validity of these scales for the detection of postnatal depression in Burkina Faso.