New approaches to the therapy of HSV infections

Two recent studies have demonstrated single-day regimens of high-dose antiviral therapy (famciclovir 1000 mg twice daily for genital herpes, and famciclovir 1500 mg single dose for herpes labialis) to be effective episodic treatment strategies. Both have the potential to improve patient compliance and therapeutic satisfaction. Patient-initiated episodic therapy (PIE) regimens such as these may improve the time to treatment initiation, which can halt lesion development: PIE allows antiviral drugs to be administered in the narrow therapeutic window that occurs early in the course of a herpes simplex virus (HSV) infection episode. This review article discusses short-course antiviral therapy, which may offer an effective alternative to traditional episodic or suppressive antiviral regimens for HSV-related disease outbreaks.     

Is your doctor competent?

HIV-positive patients are consistently healthier and live longer when their care is managed by a physician with significant experience in treating HIV and AIDS, and it is essential for patients to seek out health care providers who keep up with current treatment guidelines. Experienced doctors generally offer more aggressive treatments, and are willing to abandon treatment regimens that are not effective. Communication is essential between the patient and doctor, and must include a review of side effects and the necessity of strict adherence to treatments. A series of questions is included to help patients assess whether their doctor is up to date on current treatments.     

An update on short-course episodic and prevention therapies for herpes genitalis

The prevalence of herpes genitalis (genital herpes) has increased markedly over the past three decades. The most common cause is infection with the herpes simplex virus type 2 (HSV-2), but it can also occur as a result of HSV-1 infection. Herpes genitalis can cause substantial psychosexual as well as physical morbidity and, in immunocompromised individuals, such as those who are HIV-positive, HSV infection can result in severe disease with progressive and extensive lesions. The natural history of herpes genitalis and the pathways of infection are now well known; however, the factors associated with reactivation have yet to be fully defined. A number of management approaches with antiviral medications are commonly used, including episodic and suppressive treatments. For episodic therapy, the duration of both lesions and symptoms, as well as the proportion of aborted episodes, are the most important measures of efficacy. For suppressive therapy, the time to first recurrence and frequency of recurrences over time are the most important clinical measures of antiviral benefit. Regarding the duration of episodic regimens, comparisons of 1-, 2- and 3-day antiviral courses with standard 5-day regimens show similar benefits on healing and relief of symptoms, with the obvious improvement in convenience, economy and compliance. In HIV-positive patients, antiherpes therapy has proved effective in speeding healing of lesions and reducing subclinical shedding, and can be used to treat genital HSV-2 infections in this group. Suppressive antiviral therapy has been shown to decrease the risk of HSV transmission in heterosexual couples. New approaches to the prevention of HSV infection, including vaccines and topical microbicides, are under investigation.     

基于案例推理在艾滋病患者个性化治疗方案推荐中的应用

目的探讨艾滋病患者相似性与抗病毒治疗方案之间的关系,为制定艾滋病患者个性化治疗方案提供依据。方法收集首次接受抗病毒治疗且治疗后免疫重建良好的648例艾滋病患者临床资料,计算基于欧氏距离的患者相似性,以最相似的前10%患者治疗方案作为推荐方案,实现基于案例推理的治疗方案推荐,并通过数据可视化工具呈现基于案例推理和聚类分析的结果。结果基于患者相似性推荐的治疗方案与实际初始治疗方案的一致率达到83.3%。结论根据患者相似性推荐的治疗方案与实际的治疗方案之间具有较高的一致性,证实了基于案例推理和聚类分析在艾滋病患者个性化治疗方案推荐中的可行性和有效性,为艾滋病领域的精准医疗研究提供了参考。     

Simplifying antiretroviral therapy

The substantial benefits conferred by HAART require strict patient adherence. Many of the initial HAART regimens consisted of a number of large pills that needed to be taken several times daily, sometimes with meal restrictions. The development of once-daily antiretroviral agents has eased some of the burden associated with the intense, difficult schedules of early HAART regimens.. The majority of regimens currently used in treatment-naive HIV-positive patients contain a mixture of agents that are taken on a once- and twice-daily basis. Although this is an improvement over past regimens, the asynchronous administration of pills throughout the day still presents a scheduling challenge for most patients. The newest advance in simplifying antiretroviral therapy is the use of regimens in which all pills are taken at the same time once a day. Choosing drugs for a fully once-daily regimen requires awareness of a number of factors, including pharmacokinetics, potency, durability of response, resistance and safety. At this time, there are a limited number of combinations that can be used as a fully once-daily regimen and few clinical trials evaluating such combinations. Results from initial clinical trials using simplified, once-daily regimens in treatment-naive patients have been promising. Additional studies should add to this experience and provide guidance on the role and timing of such regimens in the management of patients with HIV disease.     

Opportunistic infections

Opportunistic infections (OIs) remain a serious problem for HIV-positive patients who remain vulnerable to fungal, parasitic, and bacterial infections. OIs continue to cause severe illness and death in many HIV-positive patients. Researchers are looking at ways to diagnose and prevent PCP, HIV-related cancers, CMV, resistant Candida, and MAC. Treatment regimens are outlined, and results from a number of studies are outlined.     

A home-based approach to managing multi-drug resistant tuberculosis in Uganda: a case report

ABSTRACT: This case report describes an HIV-positive patient with recurrent tuberculosis in Uganda. After several failed courses of treatment, the patient was diagnosed with multi-drug resistant tuberculosis (MDR-TB). As adequate in-patient facilities were unavailable, we advised the patient to remain at home, and he received treatment at home via his family and a community nurse. The patient had a successful clearance of tuberculosis. This strategy of home-based care represents an important opportunity for treatment of patients in East Africa, where human resource constraints and inadequate hospital facilities exist for complex patients at high risk of infection to others.     

Treatment of chronic hepatitis C in patients with HIV/HCV coinfection

Hepatitis C virus (HCV) infection is one of the most frequent causes of comorbidity and mortality in the human immunodeficiency virus (HIV) population, and liver-related mortality is now the second highest cause of death in HIV-positive patients, so HCV infection should be countered with adequate antiviral therapy. In 2011 began the era of directly acting antivirals (DAAs) and the HCV NS3/4A protease inhibitors telaprevir and boceprevir were approved to treat HCV-genotype-1 infection, each one in combination with pegylated interferon alfa (Peg-IFN) + ribavirin (RBV). The addition of the first generation DAAs, strongly improved the efficacy of antiviral therapy in patients with HCV-genotype 1, both for the HCV-monoinfected and HIV/HCV coinfected, and the poor response to Peg-IFN + RBV in HCV/HIV coinfection was enhanced. These treatments showed higher rates of sustained virological response than Peg-IFN + RBV but reduced tolerability and adherence due to the high pill burden and the several pharmacokinetic interactions between HCV NS3/4A protease inhibitors and antiretroviral drugs. Then in 2013 a new wave of DAAs arrived, characterized by high efficacy, good tolerability, a low pill burden and shortened treatment duration. The second and third generation DAAs also comprised IFN-free regimens, which in small recent trials on HIV-positive patients have shown comforting preliminary results in terms of efficacy, tolerability and adherence.     

Cotrimoxazole therapy ofToxoplasma gondii encephalitis in AIDS patients

Twenty-four consecutive HIV-positive patients affected byToxoplasma gondii encephalitis received trimethoprim-sulfamethoxazole (cotrimoxazole) as acute-phase treatment. Two dosage regimens of cotrimoxazole were used: 40 mg/kg/day (12 patients) or 120 mg/kg/day (12 patients) of total compound (trimethoprim plus sulfamethoxazole). Clinical and radiological responses to treatment were evaluated, and the product-limit method for survival data analysis was used. Eighteen of 24 patients showed both a clinical and radiological response (75 % response rate). There were no differences in response rates between patients receiving the two dosage regimens of cotrimoxazole. Adverse reaction consisted of leukopenia (two cases) and skin rash (three cases) which led to the discontinuation of the drug in one case. These results suggest that a randomized, controlled clinical trial should be carried out comparing cotrimoxazole versus sulfadiazine-pyrimethamine in AIDS patients withToxoplasma gondii encephalitis.Deceased.     

HIV infection--a risk factor for osteoporosis

Osteopenia and osteoporosis have recently been described as complications of antiretroviral therapy in HIV-infected patients. The advent of highly active antiretroviral therapy in conjunction with improved standard antiviral and antibiotic regimens has dramatically changed the clinical course of HIV infection, resulting in prolonged survival. The pathogenesis and role of each individual medication are poorly understood. Avascular necrosis has also been described in AIDS patients receiving or not receiving antiretroviral therapy. This article is a clinically focused review of the literature on osteopenia, osteoporosis, and mineral metabolism related to HIV infection. In patients with HIV infection, the risks of osteopenia and osteoporosis are not very clear. The suggested risk factors for the development of osteopenia are use of protease inhibitors, longer duration of HIV infection, high viral load, high lactate levels, low bicarbonate levels, raised alkaline phosphatase level, and lower body weight before antiretroviral therapy. There have also been a few case reports of pathologic fractures in AIDS patients with antiretroviral therapy-induced osteopenia and osteoporosis. The underlying mechanism triggering bone loss in HIV-infected patients is unknown. The proinflammatory cytokines tumor necrosis factor and interleukin-6 have been found to be constitutionally produced in increased amounts in HIV-positive individuals, and they may have a role in osteoclast activation and resorption. Serum markers of bone formation are decreased and resorption is increased in patients with advanced clinical disease. Hypocalcemia, hypercalcemia, and abnormalities of the parathyroid hormone axis have been described in HIV infection. Histomorphometric analyses have shown altered bone remodeling in HIV-infected patients when compared with controls. Patients with known risk factors for osteoporosis-advancing age, low body weight, and prolonged duration of HIV infection-and those receiving protease inhibitor treatment should be considered for dual x-ray absorptiometry imaging. If bone mineral density is osteopenic or osteoporotic, then the patient should also be screened for other known medical causes of osteoporosis and consider treatment with a bisphosphonate or, if hypogonadal, testosterone replacement under close monitoring.     

How hepatitis C virus counteracts the interferon response: the jury is still out on NS5A

Interferons (IFNs) induce an antiviral state in the cell through complex and indirect mechanisms, which culminate in a direct inhibition of viral replication and stimulation of the host adaptive responses. Viruses often counteract with elaborate strategies to interfere with the induction as well as action of IFN effector molecules. This evolutionary battle between viruses and IFN components is a subject of intense research aimed at understanding the immunopathogenesis of viruses and the molecular basis of IFN signaling and action. In the case with hepatitis C virus (HCV), this may have profound implications for the therapeutic use of recombinant IFN in treating chronic hepatitis C. Depending on the subtype of HCV, current IFN-based treatment regimens are effective for only a small subset of chronic hepatitis C patients. Thus, one of the Holy Grails in HCV research is to understand the mechanisms by which the virus may evade IFN antiviral surveillance and establish persistent infection, which may eventually provide insights into new avenues for better antiviral therapy. Despite the lack of an efficient tissue culture system and an appropriate animal model for HCV infection, several mechanisms have been proposed based on clinical studies and in vitro experiments. This minireview focuses on the HCV NS5A nonstructural protein, which is implicated in playing a role in HCV tolerance to IFN treatment, possibly in part through its ability to inhibit the cellular IFN-induced PKR protein kinase.     

Quantification of low levels of human immunodeficiency virus (HIV) type 1 RNA in P24 antigen-negative, asymptomatic, HIV-positive patients by PCR.

A nested PCR was used to quantify small numbers of human immunodeficiency virus (HIV) type 1 (HIV-1) RNA particles in the serum specimens of 26 p24 antigen-negative, asymptomatic, HIV-positive patients undergoing antiretroviral therapy. Fifteen patients received zidovudine (ZDV) and alpha interferon, and 11 patients received ZDV monotherapy. After PCR, the amounts of RNA were quantified by comparing the endpoint dilutions of serum samples with a standard curve with known amounts of viral particles. Before the beginning of the antiviral therapy, HIV-1 RNA was detected in 92% of the patients. After treatment, a fall in the number of viral particles was detected in patients receiving combination therapy (mean titers +/- standard errors of the means, 3,617 +/- 756 pretherapy versus 1,800 +/- 845 posttherapy; P < 0.05) and in patients receiving monotherapy (3,763 +/- 642 pretherapy versus 1,353 +/- 394 posttherapy; P < 0.05). Our results indicate that PCR with nested primers may be useful for assessing the changes in viremia in HIV-positive patients with low viral load undergoing antiviral therapy.     

Practice makes perfect: a volume-outcome study of hospital patients with HIV disease

OBJECTIVE: There is considerable evidence that patients with HIV fare better in hospitals that treat more HIV-positive patients. Yet, it is possible that much of this benefit is attributable to the care provided by physicians who treat high volumes of HIV-positive patients. This study examines the relation between 2 measures of volume (the number of HIV-positive patients treated in a hospital and the number of HIV-positive patients treated by the attending physician) and the probability of dying in the hospital. DATA: This study uses discharge data from 43,325 patients hospitalized with HIV disease in 5 states (Colorado, Maryland, New Jersey, New York, and Washington State) in 2002. These data were obtained from the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project State Inpatient Databases. STUDY DESIGN: Volume-outcome studies have demonstrated an inverse relation between the number of HIV-positive patients treated at a hospital and the mortality rate for these patients. Yet, the most current of these studies is based on data more than a decade old, and none of these account for the volume of HIV-positive patients treated by the physician. This study uses multivariate logistic regression analyses to estimate the impact of hospital and physician volume on patient mortality. RESULTS: This study found that when measures of physician and hospital volume are included in a regression equation explaining patient mortality, only the variable measuring physician volume remains statistically significant. Moreover, when a variable is defined for each patient based on the quartile rankings of the patient's hospital volume and the patient's physician volume, the quartile ranking of physician volume is a better predictor of survival than the quartile ranking of hospital volume. CONCLUSION: These findings suggest that the volume of patients treated by the attending physician is the key measure of volume associated with the survival of hospitalized HIV-positive patients.     

A correlation analysis of HHV infection and its predictive factors in an HIV-seropositive population in Yunnan,China

Human herpesviruses (HHVs) have a particularly high prevalence in certain high-risk populations and cause increased morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). Screening and treating subclinical HHV infections reduce human immunodeficiency virus (HIV) infection incidence, disease progression, and transmission. However, there are few studies on HHVs, HIV coinfection rates, and their related risk factors. We aimed to clarify the prevalence of all eight HHVs in peripheral blood samples collected from HIV-positive patients, and explore the association of HHV infection in HIV-positive patients in an HIV-seropositive population in Yunnan. We recruited 121 HIV-positive patients with highly active antiretroviral therapy (HAART) and 45 healthy individuals. All the eight HHVs were detected using polymerase chain reaction and their epidemiological information and clinical data were collected and statistically analyzed. A high prevalence of HHVs (89.3%) was observed in individuals with HIV infections and with herpes simplex virus (HSV)-2 (65.3%), and HSV-1 (59.5%) being the most common. Coinfection with more than two different HHVs was more common in patients with HIV infections receiving HAART (72.7%) than in healthy controls. Older age, being married, higher HIV-1 plasma viral loads, and use of antiviral protease inhibitors were independently correlated with an increased frequency of HHVs, but we found no association with CD4 count, WHO HIV clinical stage, and HIV infection duration. Our findings are of great significance for the prevention of HHV opportunistic infection in patients with AIDS and their clinical treatment.     

Looking at the positives: proactive management of STIs in people with HIV

Patients who are HIV-positive and co-infected with other sexually transmitted infections (STIs) are at risk of increased morbidity and mortality. This is of clinical significance. There has been a dramatic increase in the incidence of STIs, particularly syphilis, gonorrhoea, Mycoplasma genitalium and hepatitis C virus (HCV) in HIV-positive patients. The reasons for this are multifactorial, but contributing factors may include effective treatment for HIV, increased STI testing, use of HIV pre-exposure prophylaxis and use of social media to meet sexual partners. The rate of syphilis–HIV co-infection is increasing, with a corresponding increase in its incidence in the wider community. HIV-positive patients infected with syphilis are more likely to have neurological invasion, causing syndromes of neurosyphilis and ocular syphilis. HIV infection accelerates HCV disease progression in co-infected patients, and liver disease is a leading cause of non-AIDS-related mortality among patients who are HIV-positive. Since several direct-acting antivirals have become subsidised in Australia, there has been an increase in treatment uptake and a decrease in HCV viraemia in HIV-positive patients. The incidence of other sexually transmitted bacterial infections such as Neisseria gonorrhoeae and M. genitalium is increasing in HIV patients, causing urethritis, proctitis and other syndromes. Increasing antimicrobial resistance has also become a major concern, making treatment of these infections challenging. Increased appropriate testing and vigilant management of these STIs with data acquisition on antimicrobial sensitivities and antimicrobial stewardship are essential to prevent ongoing epidemics and emergence of resistance. Although efforts to prevent, treat and reduce epidemics of STIs in patients living with HIV are underway, further advances are needed to reduce the significant morbidity associated with co-infection in this patient setting.     

Interferon-Free Regimens for Hepatitis C: Combine and Conquer

Since the approval of the first direct-acting antiviral agents (DAAs), treatment for hepatitis C virus (HCV) has undergone significant transformation. A new milestone in the treatment of HCV, the approval of the first interferon-free regimens, could be achieved by the end of 2013. For patients with HCV who have absolute or relative contraindications to pegylated-interferon or have failed the currently available treatments, the arrival of new regimens will have a major impact on long-term outcomes. The combinations of DAAs in trials are numerous, and many have demonstrated sustained virologic response rates higher than 90 %. These improvements have also been observed in previous null responders and patients who failed telaprevir- or boceprevir-based regimens. Some specific subpopulations may not be perfectly served by interferon-free regimens, such as patients with genotypes 1a or 3 or cirrhosis, whereas others, such as HIV-infected patients or transplant patients, will definitively benefit from regimens with a lower burden of side effects. This paper reviews the interferon-free regimens currently in phase II or III for which sustained virologic response data are available and discusses the successes and potential pitfalls of these regimens.     

Catheter-related cutaneous aspergillosis complicated by fungemia and fatal pulmonary infection in an HIV-positive patient with acute lymphocytic leukemia

A case of intravenous catheter-related cutaneous aspergillosis andAspergillus fumigatus fungemia in an HIV-positive patient with Burkitt-cell acute lymphocytic leukemia is reported. The patient developed pulmonary aspergillosis with a rapidly fatal outcome despite recovery from neutropenia and improvement of the underlying malignancy. The unusual severity and rapid spread of the infection, despite normal neutrophil count and prompt antifungal therapy, suggest that HIV-related immunocompromise might play a role in the impairment of host defences againstAspergillus infection. Thus catheter-related cutaneous aspergillosis could lead to a severe deep-seated infection in HIV-positive patients.     

Hepatotoxicity and virological breakthrough of HCV following treatment with sofosbuvir,daclatasvir, and ribavirin in patients previously treated for tuberculosis

The prevalence of hepatitis C virus/tuberculosis (HCV/TB) coinfection has not been estimated globally but few studies highlight the risk of hepatotoxicity following TB treatment or HCV treatment. Previously reported data highlights the risk of drug-induced hepatotoxicity associated with three of the first-line anti-TB agents: rifampin, isoniazid, and pyrazinamide specifically in patients coinfected with HIV and HCV. Thus far, direct-acting antiviral (DAA) drug-induced hepatotoxicity has not been reported in the literature but herein, we observed an unusual case of HCV virological breakthrough and hepatoxicity during treatment with DAA drugs in a patient who has previously been successfully treated for TB.