Optimal Timing and Duration of Induction Therapy for HIV-1 Infection

The tradeoff between the need to suppress drug-resistant viruses and the problem of treatment toxicity has led to the development of various drug-sparing HIV-1 treatment strategies. Here we use a stochastic simulation model for viral dynamics to investigate how the timing and duration of the induction phase of induction–maintenance therapies might be optimized. Our model suggests that under a variety of biologically plausible conditions, 6–10 mo of induction therapy are needed to achieve durable suppression and maximize the probability of eradicating viruses resistant to the maintenance regimen. For induction regimens of more limited duration, a delayed-induction or -intensification period initiated sometime after the start of maintenance therapy appears to be optimal. The optimal delay length depends on the fitness of resistant viruses and the rate at which target-cell populations recover after therapy is initiated. These observations have implications for both the timing and the kinds of drugs selected for induction–maintenance and therapy-intensification strategies

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

Management of HIV-associated cryptococcal disease in South Africa

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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

Guidelines for Diagnosing and Managing Disseminated Histoplasmosis among People Living with HIV

Histoplasmosis is a disease caused by the fungus Histoplasma capsulatum . This disease is highly endemic in some regions of North America, Central America, and South America and is also reported in certain countries of Asia and Africa. It often affects people with impaired immunity, including people living with HIV, among whom the most frequent clinical presentation is disseminated histoplasmosis. The symptoms of disseminated histoplasmosis are non-specific and may be indistinguishable from those of other infectious diseases, especially disseminated tuberculosis (TB), thus complicating diagnosis and treatment. Histoplasmosis is one of the most frequent opportunistic infections caused by fungal pathogens among people living with HIV in the Americas and may be responsible for 5–15% of AIDS-related deaths every year in this Region. These guidelines aim to provide recommendations for the diagnosis, treatment, and management of disseminated histoplasmosis in persons living with HIV. Although the burden of disease is concentrated in the Americas, the recommendations contained within these guidelines are applicable globally. These guidelines were produced in accordance with the World Health Organization (WHO) handbook for guideline development. The Guideline Development Group elaborated the final recommendations based on systematic review of scientific literature and critical evaluation of the evidence available using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. These guidelines are intended for health-care providers, HIV program managers, policy-makers, national treatment advisory boards, and other professionals involved in caring for people who either have or may be at risk of developing disseminated histoplasmosi

Timing of Antiretroviral Therapy for HIV in the Setting of TB Treatment

The convergent human immunodeficiency virus (HIV) and tuberculosis (TB) pandemics continue to collectively exact significant morbidity and mortality worldwide. Highly active antiretroviral therapy (HAART) has been a critical component in combating the scourge of these two conditions as both a preemptive and therapeutic modality. However, concomitant administration of antiretroviral and antituberculous therapies poses significant challenges, including cumulative drug toxicities, drug-drug interactions, high pill burden, and the immune reconstitution inflammatory syndrome (IRIS), thus complicating the management of coinfected individuals. This paper will review data from recent studies regarding the optimal timing of HAART initiation relative to TB treatment, with the ultimate goal of improving coinfection-related morbidity and mortality while mitigating toxicity resulting from concurrent treatment of both infections

Multifarious immunotherapeutic approaches to cure HIV-1 infection

Immunotherapy in the context of treated HIV-1 infection aims to improve immune responses to achieve better control of the virus. To date, multifaceted immunotherapeutic approaches have been shown to reduce immune activation and increase CD4 T-lymphocyte counts, further to the effects of antiretroviral therapy alone, in addition to improving HIV-1-specific T-cell responses. While sterilizing cure of HIV-1 would involve elimination of all replication-competent virus, a functional cure in which the host has long-lasting control of viral replication may be more feasible. In this commentary, we discuss novel strategies aimed at targeting the latent viral reservoir with cure of HIV-1 infection being the ultimate goal, an achievement that would have considerable impact on worldwide HIV-1 infection

Major Role for Amphotericin B–Flucytosine Combination in Severe Cryptococcosis

BACKGROUND: The Infectious Diseases Society of America published in 2000 practical guidelines for the management of cryptococcosis. However, treatment strategies have not been fully validated in the various clinical settings due to exclusion criteria during therapeutic trials. We assessed here the optimal therapeutic strategies for severe cryptococcosis using the observational prospective CryptoA/D study after analyzing routine clinical care of cryptococcosis in university or tertiary care hospitals. METHODOLOGY/PRINCIPAL FINDINGS: Patients were enrolled if at least one culture grew positive with Cryptococcus neoformans. Control of sterilization was warranted 2 weeks (Wk2) and 3 months (Mo3) after antifungal therapy onset. 208 HIV-positive or -negative adult patients were analyzed. Treatment failure (death or mycological failure) at Wk2 and Mo3 was the main outcome measured. Combination of amphotericin B+flucytosine (AMB+5FC) was the best regimen for induction therapy in patients with meningoencephalitis and in all patients with high fungal burden and abnormal neurology. In those patients, treatment failure at Wk2 was 26% in the AMB+5FC group vs. 56% with any other treatments (p<0.001). In patients treated with AMB+5FC, factors independently associated with Wk2 mycological failure were high serum antigen titer (OR [95%CI] = 4.43[1.21-16.23], p = 0.025) and abnormal brain imaging (OR = 3.89[1.23-12.31], p = 0.021) at baseline. Haematological malignancy (OR = 4.02[1.32-12.25], p = 0.015), abnormal neurology at baseline (OR = 2.71[1.10-6.69], p = 0.030) and prescription of 5FC for less than 14 days (OR = 3.30[1.12-9.70], p = 0.030) were independently associated with treatment failure at Mo3. CONCLUSION/SIGNIFICANCE: Our results support the conclusion that induction therapy with AMB+5FC for at least 14 days should be prescribed rather than any other induction treatments in all patients with high fungal burden at baseline regardless of their HIV serostatus and of the presence of proven meningoencephalitis