Antiviral agents and HIV prevention: controversies, conflicts, and consensus

Antiviral agents can be used to prevent HIV transmission before exposure as preexpo-sure prophylaxis (PrEP), after exposure as postexposure prophylaxis, and as treatment of infected people for secondary prevention. Considerable research has shed new light on antiviral agents for PrEP and for prevention of secondary HIV transmission. While promising results have emerged from several PrEP trials, the challenges of poor adherence among HIV-negative clients and possible increase in sexual risk behaviors remain a concern. In addition, a broader pipeline of antiviral agents for PrEP that focuses on genital tract pharmacology and safety and resistance issues must be developed. Antiretroviral drugs have also been used to prevent HIV transmission from HIV-infected patients to their HIV-discordant sexual partners. The HIV Prevention Trials Network 052 trial demonstrated nearly complete prevention of HIV transmission by early treatment of infection, but the generalizability of the results to other risk groups – including intravenous drug users and MSM – has not been determined. Most importantly, the best strategy for use of antiretroviral agents to reduce the spread of HIV at either the individual level or the population level has not been developed, and remains the ultimate goal of this area of investigation

HIV Reservoirs and Immune Surveillance Evasion Cause the Failure of Structured Treatment Interruptions: A Computational Study

Continuous antiretroviral therapy is currently the most effective way to treat HIV infection. Unstructured interruptions are quite common due to side effects and toxicity, among others, and cannot be prevented. Several attempts to structure these interruptions failed due to an increased morbidity compared to continuous treatment. The cause of this failure is poorly understood and often attributed to drug resistance. Here we show that structured treatment interruptions would fail regardless of the emergence of drug resistance. Our computational model of the HIV infection dynamics in lymphoid tissue inside lymph nodes, demonstrates that HIV reservoirs and evasion from immune surveillance themselves are sufficient to cause the failure of structured interruptions. We validate our model with data from a clinical trial and show that it is possible to optimize the schedule of interruptions to perform as well as the continuous treatment in the absence of drug resistance. Our methodology enables studying the problem of treatment optimization without having impact on human beings. We anticipate that it is feasible to steer new clinical trials using computational models

Caffeine Intake and its Association with Disease Progression, Sleep Quality and Anxiety Symptoms and Nutritional Alterations in People Living with HIV in the Miami Adult Studies on HIV Cohort

Miami-Dade County has approximately 27,000 people living with HIV (PLWH), and the highest HIV incidence in the nation. PLWH have reported several types of sleep disturbances. Caffeine is an anorexic and lipolytic stimulant that may adversely affect sleep patterns, dietary intakes and body composition. High caffeine consumption (\u3e250 mg. per day or the equivalent of \u3e4 cups of brewed coffee) may also affect general functionality, adherence to antiretroviral treatment (ART) and HIV care. This study assess the relationship of high caffeine intake with markers of disease progression, sleep quality, insomnia, anxiety, nutritional intakes and body composition. A convenience sample of 130 PLWH on stable ART were recruited from the Miami Adult Studies on HIV (MASH) cohort, and followed for three months. After consenting, questionnaires on Modified Caffeine Consumption (MCCQ), Pittsburg Insomnia Rating Scale (PIRS), Pittsburg Sleep Quality Index (PSQI), Generalized Anxiety Disorder-7 (GAD-7), socio-demographics, drug and medication use were completed. CD4 count, HIV viral load, anthropometries, and body composition measures were obtained. Mean age was 47.89±6.37 years, 60.8% were male and 75.4% were African-Americans. Mean caffeine intake at baseline was 337.63 ± 304.97 mg/day (Range: 0-1498 mg/day) and did not change significantly at 3 months. In linear regression, high caffeine consumption was associated with higher CD4 cell count (β=1.532, P=0.049), lower HIV viral load (β=-1.067, P=0.048), higher global PIRS (β=1.776, P=0.046), global PSQI (β=2.587, P=0.038), and GAD-7 scores (β=1.674, P=0.027), and with lower fat mass (β=-0.994, P=0.042), energy intakes (β=-1.643, P=0.042) and fat consumption (β=-1.902, P=0.044), adjusting for relevant socioeconomic and disease progression variables. Over three months, these associations remained significant. The association of high caffeine with lower BMI weakened when excluding users of other anorexic and stimulant drugs such as cocaine and methamphetamine, suggesting that caffeine in combination, but not alone, may worsen their action. In summary, high caffeine consumption was associated with better measures of disease progression; but was also detrimental on sleep quality, nutritional intakes, BMI and body composition and associated with insomnia and anxiety. Large scale studies for longer time are needed to elucidate the contribution of caffeine to the well-being of PLWH

The scale-up of PrEP for HIV prevention in high-risk women in sub-Saharan Africa: use of mathematical modelling to inform policy making

Background: Women in sub-Saharan Africa carry a disproportionate burden and risk of HIV. In this context, women at high HIV risk are not a discrete group, rather on a spectrum of risk caused by a multitude of behavioural, economic, structural, cultural and geographic factors. Pre-exposure prophylaxis (PrEP) is a promising new HIV prevention method, effective at reducing HIV risk when adhered to. However, the results of PrEP trials and implementation studies to date reveal challenges in women’s programme retention and drug adherence. There are also concerns that behavioural disinhibition (reductions in condom use) following the introduction of PrEP may further limit its ability to avert infections. In the context of HIV resource limitations and decreasing donor budgets, this thesis seeks to use mathematical modelling to assess strategies for PrEP scale-up for women across a spectrum of risk in sub-Saharan Africa, accounting for heterogeneities in HIV risk factors and PrEP programme outcomes. Considering the challenges faced by policy makers in using mathematical models to guide decision making, often considered to be complex ‘black boxes’, this thesis also sets out to assess the contexts in which simple models are sufficient to guide policy making around the introduction of a new HIV prevention intervention. Methods: This thesis adopts mathematical modelling approaches to inform HIV policy making. First, a simple static model of HIV risk to female sex workers is developed and used to assess the impact of behavioural disinhibition on PrEP’s ability to avert HIV infections. The static model formulation is then evolved to incorporate dynamic effects to account for the downstream effects of population interactions. The models account for heterogeneities in women’s HIV risk factors and PrEP programme outcomes, and the low levels of PrEP programme retention and adherence reported in studies. The outcomes of the static and dynamic model formulation are compared over different time horizons and epidemic contexts, to contribute to understanding around the importance of modelling complexity to inform HIV policy. Finally, the static model is refined to represent women across a more broadly defined spectrum of risk: women 15-24 years, 25-34 years, 35-49 years and female sex workers. The models are parameterised to case study countries spanning a range of high HIV burden contexts in sub-Saharan Africa: South Africa, Zimbabwe and Kenya, and used to assess strategies for PrEP scale-up in each country, considering cost-effectiveness and population-level impact. Conclusions: PrEP is likely to be of benefit in reducing HIV risk in women across a spectrum of HIV-risk in sub-Saharan Africa, even if reductions in condom use occur. PrEP will be most cost-effective for individuals at great HIV risk, such as female sex workers. However, PrEP has potential to significantly reduce the number of new infections at population-level if made widely available beyond those at highest individual risk, including to women in the general population. Strategies for PrEP scale-up will need to weigh the potential cost-effectiveness and population-level impact of PrEP with the potential for PrEP integration into a wide range of national services and at community level, in order to significantly bring down the costs and improve cost-effectiveness in resource-constrained environments. Static models can be sufficiently robust to inform policy making around the introduction of new HIV prevention interventions in high HIV-burden settings over short-medium time horizon of up to 5 years, where underlying HIV epidemics have reached equilibrium. Over longer timeframes, and in contexts where the underlying HIV epidemics are still evolving (other than over short time horizons of less than a year), static models may under-emphasize situations of programmatic importance and dynamic models will be more appropriate to guide decision making

Understanding the acceptability and utility of early antiretroviral therapy to reduce transmission of HIV amongst men who have sex with men in the UK

High viraemia in early HIV infection (EHI) may contribute disproportionately to onward transmission in men who have sex with men (MSM) but early antiretroviral therapy (ART) could minimise risk of transmission. The effectiveness of this strategy depends on viral load (VL) at presentation, sexual behaviour and ART acceptability, which are unknown. This thesis combines quantitative and qualitative methods to understand the acceptability and utility of early ART to reduce HIV transmission in UK MSM. Using UK Register of HIV Seroconverters data I examined temporal trends in ART initiation and VL at presentation, using Kaplan-Meier and logistic regression. An in-depth interview and cross-sectional survey explored and quantified men’s attitudes, beliefs and acceptability of early ART and sexual behaviour. Using logistic regression I examined factors associated with early ART initiation and high-risk sex post diagnosis. VL peaked in men presenting ~30 days post-seroconversion, plateauing ~day 100. Median(95% CI) time from seroconversion to ART initiation decreased, from 3.7(3.2,4.9) years pre-2000 to 1.4(1.3,1.7) in 2010-11. Early ART was acceptable; 67%(76/114) would have accepted it at diagnosis and 47%(55/116) had initiated it. ART initiation was more likely if men believed it had health benefits or their clinician recommended it. It was perceived to reduce transmission anxiety and provide holistic health benefits, but fear of toxicities and stigma were potential barriers to initiation. Transmission risk was low postdiagnosis; 32%(37/117) abstained from sex and 21%(24/117) exclusively used condoms. However, 35%(41/117) reported high-risk sex, associated with treatment optimism, ChemSex and higher partner numbers pre-diagnosis. Early ART was acceptable to MSM to prevent transmission, and for perceived holistic health benefits. It is unlikely, however, to be effective in reducing transmission risk during peak viraemia given the low proportion presenting at that stage. Expansion of HIV testing is required to identify MSM during that stage

Evaluating HIV treatment as prevention in the European context

Executive summary The goal of this project is to gather evidence regarding the population-level, and to some extent, individual-level effects of the use of antiretroviral treatment (ART) to prevent HIV infection, and to relate this to current HIV treatment guidelines. To inform the project, formal literature reviews were performed for the three main areas of interest: the effect of antiretroviral therapy in adults on preventing sexual transmission of HIV, prevention of mother-to-child transmission (pMTCT) and post exposure prophylaxis (PEP). The strongest evidence with regard to the effect of treatment of HIV positive individuals to prevent onwards sexual transmission comes from the recent randomised controlled trial (RCT), HPTN052. This study demonstrated that early versus delayed ART led to a 96% relative reduction in onwards linked transmission. Several observational studies of HIV sero-discordant heterosexual couples have also reported that transmission is rare in patients on ART, particularly in those with low HIV-RNA concentrations. However, the findings of HPTN052 and these observational studies are mainly applicable to vaginal heterosexual sex. No direct empirical evidence regarding the relationship between ART use and the risk of HIV transmission through anal intercourse is currently available. Whilst the major HIV treatment guidelines do not explicitly recommend prescribing antiretroviral treatment to prevent onwards transmission, they do not rule out individuals starting ART at a high CD4 count on a case-by-case basis. However, one must also consider the impact of earlier treatment on the HIV positive individual with regard to side effects, and development of drug resistance. Early studies showed that pMTCT regimens containing a single antiretroviral agent (short course zidovudine or single dose nevirapine) or two antiretroviral agents (zidovudine and lamivudine with or without single dose nevirapine) led to clinically important reductions in MTCT rates. However, the most substantial reductions in MTCT rates occurred when combination antiretroviral regimens (more than three antiretroviral drugs) were introduced. These regimens involve the receipt of ART before the third trimester of pregnancy, intrapartum treatment, maternal post-partum treatment and some form of neonatal treatment. There is some evidence from RCTs and extensive evidence from observational studies of the efficacy of these combination regimens, with very low rates of transmission of around 0% to 6%, in settings with no or very little breastfeeding, and 1%-9% when breastfeeding occurs. Furthermore, in settings where avoidance of breastfeeding is not possible, there are a number of studies demonstrating that receipt of maternal and/or neonatal ART during the six months after birth can reduce the risk of perinatal transmissions. All treatment guidelines recommend that HIV-positive pregnant women should receive ART to prevent MTCT, although the exact timing of when ART should begin is not always explicit. Furthermore, where mentioned, use of neonatal ART is also recommended, regardless of whether infants are breastfed. Much of the data supporting the use of PEP are based on animal models, which suggest that PEP is most efficacious if commenced as soon as possible after exposure. When considering occupational exposure to HIV, human studies are limited, as no RCTs exist for ethical reasons. Evidence for efficacy is based on one case control study which demonstrated an 81% reduction in transmission of HIV through the use of zidovudine. Other studies have demonstrated that PEP following occupational exposure is not always effective and there are cases of PEP failure. Similarly, there are also no RCTs assessing the efficacy of PEP for prevention of HIV transmission after sexual exposure, and limited evidence from observational data. Most treatment guidelines agree that PEP is not always effective and PEP policies need to emphasise the importance of risk prevention in the first place in all settings where there is a risk of HIV transmission. Side effects are not uncommon when using PEP, so it is important to consider carefully whether an individual should receive PEP and some studies have suggested that increase in availability of PEP may lead to an increase in risky sex behaviour. Antiretroviral treatment has well documented benefits in reducing transmission of HIV and, in particular, has had a major population level impact on HIV acquisition in children from HIV positive mothers. Further research is needed to help us understand how we can best use ART to prevent HIV infections through other transmission routes, and to develop evidence-based policy recommendations, particularly in the European context

Current Perspectives in HIV Infection

This book gives a comprehensive overview of HIV and AIDS including NeuroAIDS, as well as general concepts of pathology, immunity and immunopathology, diagnosis, treatment, epidemiology and etiology to current clinical recommendations in management of HIV/AIDS including NeuroAIDS, highlighting the ongoing issues, recent advances and future directions in diagnostic approaches and therapeutic strategies

PLoS One

Inferring disease transmission networks is important in epidemiology in order to understand and prevent the spread of infectious diseases. Reconstruction of the infection transmission networks requires insight into viral genome data as well as social interactions. For the HIV-1 epidemic, current research either uses genetic information of patients' virus to infer the past infection events or uses statistics of sexual interactions to model the network structure of viral spreading. Methods for a reliable reconstruction of HIV-1 transmission dynamics, taking into account both molecular and societal data are still lacking. The aim of this study is to combine information from both genetic and epidemiological scales to characterize and analyse a transmission network of the HIV-1 epidemic in central Italy.We introduce a novel filter-reduction method to build a network of HIV infected patients based on their social and treatment information. The network is then combined with a genetic network, to infer a hypothetical infection transmission network. We apply this method to a cohort study of HIV-1 infected patients in central Italy and find that patients who are highly connected in the network have longer untreated infection periods. We also find that the network structures for homosexual males and heterosexual populations are heterogeneous, consisting of a majority of 'peripheral nodes' that have only a few sexual interactions and a minority of 'hub nodes' that have many sexual interactions. Inferring HIV-1 transmission networks using this novel combined approach reveals remarkable correlations between high out-degree individuals and longer untreated infection periods. These findings signify the importance of early treatment and support the potential benefit of wide population screening, management of early diagnoses and anticipated antiretroviral treatment to prevent viral transmission and spread. The approach presented here for reconstructing HIV-1 transmission networks can have important repercussions in the design of intervention strategies for disease control

The proportional contribution of disease stage and antiretroviral treatment to HIV transmission in men who have sex with men: an epidemiological phylogenetic approach incorporating the enhanced identification of recent infection.

AIM: This work identifies recent HIV infection (RHI) in men who have sex with men (MSM) and the specific phylogenetically-linked transmission events during which they were infected. The overall aim is to identify the clinical characteristics of each infection source individual and evaluate their proportional contribution to transmission. OBJECTIVES: 1. Construct a dataset to capture cohort characteristics; 2. Identify RHI in subtype B infection using the Serological Testing Algorithm for Recent HIV Seroconversion (STARHS); 3. Identify the most-likely infection source individual for each RHI by phylogenetic analysis; 4. Observe the clinical characteristics of each infection source individual at the time of infection and estimate the proportional contribution to transmission of unknown infection, disease stage and HAART status METHODOLOGY: The study population was a cohort of mainly MSM attending the single HIV clinic in Brighton, UK. The study involved phylogenetic analysis of HIV genotypic sequences obtained for routine clinical care. Clinical data were also collected. Written, informed consent was obtained and every study described in this thesis had formal ethical approval. RESULTS: 1. STARHS confirmed RHI in 71/74 (96%) individuals identified as RHI by conventional methods; 2. Pol sequence data were obtained for 859/1144 (75%), of whom 159/859 (19%) were RHI at diagnosis; 3. For only 41/159 (26%) RHI could an infection source individual be identified; 4. RHI contributed 3% of follow-up time but 41/59 (27%) transmissions (RR 4.44, 95% CI 2.11-9.33, p=0.0001); 5. 39/41 (95%) transmissions were from untreated individuals or those interrupting antiretroviral treatment (ART). CONCLUSIONS: Three-quarters of infections came from undiagnosed infections or from outside Brighton. Of those from diagnosed infections, transmission was significantly associated with RHI, STI and viral load, and reduced by effectively-taken ART. These results demonstrate that effective behavioural interventions to increase HIV testing and improve ART uptake and adherence will reduce onward transmission