Guidance for National Tuberculosis Programmes on the management of tuberculosis in children - an update

About one million children develop tuberculosis (TB) annually worldwide. Childhood TB is common in Malawi accounting for about 12% of all TB cases. Childhood TB differs from TB in adults in ways that have important implications for the prevention, diagnosis and treatment of TB in children. Young children living in close contact with a case of smear-positive pulmonary TB are at particular risk of infection and TB disease. Screening of the household contacts of an infectious source case is therefore recommended to identify children with TB and enable their prompt treatment, and to provide children who do not have TB with isoniazid preventive treatment. It is recognised that there is a need to improve the diagnosis and management of children with TB, the prevention of TB in children and to ensure their inclusion under the implementation of the Stop TB strategy by National TB Programmes. A subgroup of the WHO DOTS Expansion Working Group called the Stop TB Partnership Childhood TB Subgroup published guidelines for the management of child TB in 2006. The guidelines are designed to complement current national and international guidelines on the implementation of the Stop TB Strategy and existing guidelines, but also to fill existing gaps to ensure that children with M. tuberculosis infection and TB disease are identified early and managed effectively. This paper summarises some of the most important information and recommendations put forward in those guidelines.     

Changes in Escherichia coli resistance to co-trimoxazole in tuberculosis patients and in relation to co-trimoxazole prophylaxis in Thyolo,Malawi

In Thyolo district, Malawi, an operational research study is being conducted on the efficacy and feasibility of co-trimoxazole prophylaxis in preventing deaths in HIV-positive patients with tuberculosis (TB). A series of cross-sectional studies were carried out to determine i) whether faecal Escherichia coli (E.coli) resistance to co-trimoxazole in TB patients changed with time and ii) whether the resistance pattern was different in HIV positive TB patients who were taking co-trimoxazole prophylaxis. Co-trimoxazole resistance among E.coli isolates in TB patients at the time of registration was 60% in 1999 and 77% in 2001 (p<0.01). Resistance was 89% among HIV-infected TB patients (receiving co-trimoxazole), while in HIV negative patients (receiving anti-TB therapy alone) it was 62% (p<0.001). The study shows a significant increase of E.coli resistance to co-trimoxazole in TB patients which is particularly prominent in HIV infected patients on co-trimoxazole prophylaxis. Since a high degree of plasmid-mediated transfer of resistance exists between E.coli and the Salmonella species, these findings could herald limitations on the short and long term benefits to be anticipated from the use of co-trimoxazole prophylaxis in preventing non-typhoidal salmonella bacteraemia and enteritis in HIV infected TB patients in Malawi.     

HIV-TB: the 'cursed duet'

Tuberculosis is the most common infection among HIV-infected patients in India. More deaths were reported due to tuberculosis in AIDS patients in pre-antiretroviral therapy era. HIV is the strongest of all known, risk factors for the development of TB. Tuberculosis can develop at any stage of the HIV disease. Extrapulmonary tuberculosis is more common and constitues half of the cases in HIV-infected individual with TB. Hilar lymphadenopathy is frequently observed. TB in HIV frequently poses a diagnostic challenge. Acid-fast bacillus demonstration on sputum smear microscopy is the main-stay laboratory investigation for TB. In addition to antituberculous therapy, antiretroviral therapy must be initiated in HIV-infected individual with TB. Early referrals to the RNTCP and ART programmes are the best option for management.     

Childhood tuberculosis in Malawi: caseload,diagnostic practices and treatment outcomes

There were 22,982 cases of TB registered in Malawi in 1998, of which 2739 (11.9%) were children. Children accounted for 11.3% of all case notifications with smear-positive pulmonary TB (PTB), 21.3% with smear-negative PTB and 15.9% with extrapulmonary TB (EPTB). A significantly higher proportion of TB cases were diagnosed in central hospitals. Only 45% of children completed treatment. There were high rates of death (17%), default (13%) and unknown treatment outcomes (21%). Treatment outcomes were worse in younger children and in children with smear-negative PTB. In 2001, all 44 non-private hospitals in Malawi that register and treat children with tuberculosis (TB) were surveyed to determine actual diagnostic practice. This cross sectional study identified 150 children aged 14 years or below in hospital receiving anti-TB treatment, 98 with pulmonary TB (PTB) and 52 with extrapulmonary TB (EPTB). Median duration of illness was 8 weeks. Most patients had fever, no response to anti-malarial treatment and antibiotics, and 40% had a positive family history of TB. Nearly 45% had weight for age < 60%. Diagnosis was mainly based on clinical features and radiography, with less than 10% having tuberculin skin tests or HIV serology, and very few having other sophisticated investigations. Diagnostic difficulties make it difficult to accurately define the actual burden of childhood TB in Malawi. Diagnostic practices are poor and treatment outcomes unsatisfactory.     

Non-Tuberculous Mycobacterial Pulmonary Disease identified during community-based screening for Mycobacterium Tuberculosis: a case report

There is a rising prevalence of Non-Tuberculous Mycobacterial (NTM) disease in sub-Saharan Africa identified on culture specimens. However, distinguishing mycobacterial colonisations from infection from identified NTMs on culture in the sub-Saharan Africa setting remains to be established. A 49-year-old man presented with the cardinal symptoms of tuberculosis (TB) in a community TB prevalence survey in Blantyre, Malawi. Mycobacteriology was atypical, prompting a line probe assay which revealed Mycobacterium avium complex (MAC) species.The epidemiology of Mycobacterium tuberculosis complex (MTBC) is better known than that of NTM. Up-scaling culture and speciation may be a solution to this gap in knowledge of the burden of disease of NTM. Like most resource-poor settings, TB culture is not routinely done in the diagnosis and management of TB in Malawi. Furthermore, the treatment of NTM is not analogous to that of MTBC. The multi-drug regimens used for NTM disease treatment includes a newer macrolide (azithromycin, clarithromycin), ethambutol, and rifamycin, and require prolonged durations of therapy aimed at facilitating clearance of the mycobacteria and minimizing the emergence of drug resistance. Clinicians must thus be aware of this rising burden of NTM disease and consider other diagnostic options to better investigate this disease in patients.     

HIV/TB in India: a public health challenge

The impact of HIV/AIDS epidemic on the epidemiology of TB worldwide is being noted with growing concern. Patients with HIV are more susceptible to opportunistic diseases including TB. The risk of development of TB in HIV-infected patients in India is 6.9/100 person-years compared to a 10% lifetime risk of developing TB in an HIV negative individual with Mycobacterium tuberculosis. Treatment with DOTS significantly prolongs the life of HIV-infected persons with TB. The Government of India emphasised the need for strengthening collaboration between TB and AIDS control programmes for better management of HIV-infected patients with TB. Areas with higher prevalence of HIV infection have been prioritised the RNTCP coverage and most are already implementing the RNTCP. The basic purpose of HIV-TB programme co-ordination is to ensure optimal synergy between the two programmes for prevention and control of both the diseases.     

Human immunodeficiency virus and hepatitis C virus co-infection

Hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma worldwide, as well as the leading cause of liver transplantations in the United States. As a result of similar modes of transmission, approximately 30% of HIV-infected individuals are co-infected with HCV. Among intravenous drug users, almost 90% of people infected with HIV are also infected with HCV. Because of treatment with highly active anti-retroviral therapy, HIV-infected individuals have improved survival and are no longer suffering from opportunistic infections and malignancy as in years past. As a result, co-infection with HCV has now become a frequent cause of morbidity and mortality in HIV-infected individuals. Furthermore, liver disease secondary to HCV infection is now the leading cause of hospital deaths in HIV-infected people in the US. HIV infection accelerates the course of HCV-related liver disease and viremia. It is less clear whether HCV infection affects the clinical course of HIV; however, HCV-related liver disease can limit many individuals from receiving anti-HIV therapy. HIV/ HCV co-infection is common, and serious. Physicians caring for HIV-infected patients worldwide must now address hepatitis C virus co-infection.     

Care of women infected with the human immunodeficiency virus

OBJECTIVE.--To review current knowledge regarding human immunodeficiency virus (HIV) infection in women and to derive from that data standards of care. DATA SOURCES.--Selective review of pertinent articles addressing cervical disease, pelvic inflammatory disease, sexually transmitted diseases, contraception, and pregnancy in HIV-infected women. A computer-assisted search was used to identify relevant articles on pharmacokinetics of drugs in women and oral contraceptive--drug interactions. DATA EXTRACTION.--Pertinent data were abstracted from case-control, cohort studies, clinical trials, and pharmacokinetic studies. DATA SYNTHESIS.--Few studies have been performed to define the clinical course of HIV infection in women. Gender-specific manifestations, such as cervical neoplasia, pelvic inflammatory disease, and vaginal moniliasis, appear to pursue a more aggressive course in HIV-infected women. Little is known about the pharmacokinetics of drugs for HIV and related infections. Oral contraceptives may alter the metabolism of some drugs used in HIV-infected women. An approach to the routine treatment of HIV-infected women is summarized. CONCLUSIONS.--Little is currently known regarding the natural course of HIV infection in women. Women infected with HIV should be followed up frequently with specific attention paid to the reproductive system. Additional studies should be conducted to determine the impact of HIV on gender-specific diseases.     

Tuberculosis and HIV illness

The HIV infection leading to AIDS is considered to be one of the greatest biomedical challenges in the present century. Like all other communicable diseases AIDS is gradually penetrating the underprivileged sections of society in all countries. Nearly 5 million people in India are living with AIDS at present that makes India a single country with highest number of HIV infected people in the world. The hallmark of HIV disease is the reduction of CD4+ T-lymphocytes, the key cells of immunity. The initial phase of the disease may be termed as HIV seroconversion illness. The next phase is termed asymptomatic HIV infection. When the CD4 count falls below 400/microliter, the patient develops early opportunistic infections which may be termed as early symptomatic HIV infection or AIDS related complex (ARC). Mycobacterial infections are also common in these patients and have led to an alarming resurgence of tuberculosis (TB) in many countries. The available information suggests that TB may be the commonest HIV related disease in the world. The clinical presentation of TB in HIV infected individual is influenced by the degree of HIV related immunosuppression. The atypical features like extrapulmonary TB and absence of positive Mantoux test are generally noticed at a fairly advanced stage. The x-ray chest is also an important adjunct to diagnosis of TB in HIV infected individual. The studies on TB and AIDS in the early part of HIV epidemic in developed countries suggest that extrapulmonary TB is more common in co-infected people but when TB infection is considered in all HIV infected persons, extrapulmonary TB is less common than pulmonary TB. The result of treatment in co-infected pulmonary TB cases is almost similar with the cases suffering from TB alone. Treatment failure, however, has been noticed rarely at extrapulmonary sites.     

A Retrospective Study of Culture-confirmed Mycobacterial Infection among Hospitalized HIV-infected Patients in Beijing,China

A retrospective analysis was performed in two major HIV/AIDS referral hospitals in Beijing to evaluate the prevalence of Mycobacterium tuberculosis (MTB) and non-tuberculous mycobacterial (NTM) infections in HIV-infected patients. A total of 627 patients' data were reviewed, and 102 (16.3%) patients were diagnosed with culture-confirmed mycobacterial infection, including 84 with MTB, 16 with NTM, and 2 with both MTB and NTM. The most frequent clinical complication by mycobacterial infection was pulmonary infection (48/102, 47.1%). The overall rates of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) were 11.9% and 3.4%, respectively. This study underlines the urgent need to intensify screening for mycobacteria coinfection with HIV and to prevent the spread of drug-resistant TB among HIV-infected patients.     

The impact of HIV infection on the clinical presentation of severe malnutrition in children at QECH

A study was undertaken in a central nutritional rehabilitation unit (NRU) in southern Malawi to assess the impact of HIV infection on clinical presentation and case fatality rate. The HIV seroprevalence for 250 severely malnourished children over 1 year of age was 34.4% and the overall mortality was 28%. HIV infection was significantly more associated with marasmus (62.2%) than with kwashiorkor (21.7%) [p<0.0001]. Clinical and radiological features were not helpful in distinguishing HIV infected from non HIV infected children. The in-hospital case fatality rate was significantly higher for HIV infected children (38.4%) compared to severely malnourished children without HIV infection (22.7%) [p<0.05]. Though HIV infection contributes to the high mortality experienced in NRU''s in Malawi, we argue that more remediable contributing factors still need to be addressed.     

Guidelines for screening, prophylaxis and critical information prior to initiating anti-TNF-alpha treatment

These national clinical guidelines outlining the screening, prophylaxis and critical information required prior to initiating anti-TNF-alpha treatment have been approved by the Danish Society for Gastroenterology. Anti-TNF-alpha therapy is widely used in gastroenterology (for inflammatory bowel disease), rheumatology (for rheumatoid arthritis, psoriatic arthritis and spondyloarthropathies) and dermatology (for psoriasis). With this background, the Danish Society for Gastroenterology established a group of experts to assess evidence for actions recommended before treatment with anti-TNF-alpha agents. Screening should take place for both active tuberculosis and latent tuberculosis. Screening must evaluate the risk of hepatitis B exposure/infection and that of other viral infections such as human immunodeficiency virus (HIV) and varicella zoster virus (VZV). The assessment should include a history of previous malignancies (cases of malignant disease within 5 years of anti-TNF-alpha treatment should be carefully considered). The physical examination should include lung/heart auscultation and lymph node examination, and the paraclinical investigations should include chest X-rays and laboratory tests, including an interferon gamma release assay, a hepatitis B test, an HIV test and, when prior VZV infection is uncertain, a VZV antibody test. Prophylaxis: Isoniazid should be administered in cases of suspected latent TB infection. Antiviral treatment is recommended in HBsAg-positive patients at the start of anti-TNF-alpha treatment. Before anti-TNF-alpha therapy, vaccination with 23-valent pneumococcal vaccine is recommended, and HBV vaccination may be considered in seronegative patients. Annual vaccination against seasonal influenza is recommended. Human papilloma virus vaccination should be administered in accordance with the guidelines of the National Board of Health of Denmark. In patients without a prior VZV infection, VZV vaccination may be considered. Information for patients: Anti-TNF-alpha treatment results in a generally increased risk of infection and latent tuberculosis flare-up. Women are advised to comply with the national guidelines for screening for cervical cancer, and their HPV immunisation status should be clarified. An increased risk of lymphoma with biological therapy in combination with thiopurines should be mentioned. Patients are advised to seek medical advice in case of herpes zoster infection.     

Early diagnosis of perinatal HIV infection by detection of viral-specific IgA antibodies.

OBJECTIVES--To evaluate the clinical utility of a human immunodeficiency virus (HIV)-IgA serological assay for diagnosis of perinatally acquired HIV infection. DESIGN--Coded serum samples prospectively collected from children born to HIV-infected mothers and uninfected mothers were analyzed by HIV-IgA immunoblot. SETTING--A university hospital in Baltimore, Md, and an outpatient clinic in Port-au-Prince, Haiti. POPULATION--Five hundred thirty-nine serum samples were obtained sequentially from 278 children born to HIV-infected women (116 from The Johns Hopkins Hospital and 62 from Port-au-Prince) and from 42 control children born to HIV-seronegative children in Port-au-Prince. OUTCOME MEASURES--Results from the HIV-IgA serological assays were compared with the known infection status of the child at 15 months of age as determined by the standard IgG Western blot and the clinical classification of the Centers for Disease Control. Sensitivity, specificity, and predictive values were calculated at different ages and collectively for children 3 months of age or older. RESULTS--The HIV-IgA assay was positive in one of six specimens from HIV-infected children under 1 month of age, six of nine specimens from infected children at 3 months of age, and 160 of 161 specimens from 47 HIV-infected children 6 months of age or older. Of 334 specimens from 243 uninfected children, 333 were negative by the HIV-IgA assay. The overall sensitivity and the specificity of the IgA assay for children older than 3 months of age were 97.6% and 99.7%, and the positive and negative predictive values were 99.4% and 98.7%, respectively. CONCLUSION--Although the HIV-IgA assay had a low sensitivity within the first months of life, the high sensitivity, specificity, and predictive values of this assay demonstrate its utility for the diagnosis of perinatally acquired HIV infection after the third month of age. Early diagnosis with this relatively simple and inexpensive serological assay should aid in the implementation of antiviral therapy and provide useful information for the care of children born to HIV-infected mothers in both developing and developed countries.     

Pediatric HIV infection. An update.

Human immunodeficiency virus infection is a leading cause of immunodeficiency in children. The epidemic in children parallels that in women since most infected women are in the child-bearing age groups. The risk of vertical transmission of HIV from an infected mother to her infant ranges from 13% to 39%. Diagnosis of infection in the infant is complicated by the passive transfer of antibody across the placenta, making the use of standard serologic tests to confirm infection difficult. In children less than 15 months of age, a positive p24 core antigen test, a positive viral culture or AIDS defining criteria with immune abnormalities are required for diagnosis. HIV infection in children is chronic and multisystem characterized by immunologic and clinical deterioration with a higher incidence of serious bacterial infections, neurologic disease, and lymphoid interstitial pneumonitis. The cornerstones of management include close medical follow-up, good nutrition, and prompt diagnosis and treatment of infections. Certain children will benefit from therapeutic modalities such as Pneumocystis carinii pneumonia prophylaxis and/or intravenous gamma globulin. The antiretroviral drugs have improved the quality of life and increased survival. Several newer antiviral agents are presently in clinical trials.     

河北省平山县肺结核病人HIV感染状况筛查结果分析

目的了解平山县肺结核病人中HIV感染状况,为制定防治对策提供依据。方法选择2009年5月1日-2012年11月30日平山县疾控中心结核病门诊登记的850例肺结核病人按照知情同意原则进行HIV抗体筛查。结果850例肺结核病人中检出HIV抗体阳性者4例,阳性率为0．47％,4例病例已全部进入艾滋病期;TB／HIV双重感染病人均无固定职业,文化程度较低,以青壮年男性为主,检出的4例TB／HIV双感病人具备主动实施的高危行为史,HIV感染方式以性传播为主。结论平山县结核病人中存在HIV双重感染,对肺结核患者应加强健教宣传、HIV抗体监测及管理。     

Cases of human immunodeficiency virus infection and tuberculosis--early experiences of different aspects

An outpatients department based survey conducted in Calcutta amongst 1349 established cases of tuberculosis (TB) revealed 0.67% human immunodeficiency virus (HIV) infected cases. Those affected by HIV and TB did not show any deviation from epidemiological pattern of HIV infection in India. All contracted HIV infection by heterosexual route, mostly from Bombay (47.8%) followed by West Bengal (30.4%). In follow-up study of a cohort of 36 HIV seropositives over 3 years, 10(27.7%) developed TB. Of the 23 HIV infected cases with TB, lesions were mostly pulmonary (n = 18, 78.3%) followed by pleural effusion (n = 3;13%). Low incidence of Mycobacterium avium (intracelluarae) complex and tuberculous lymphadenopathy one case each and 52.2% positivity with 14.5 mm mean induration diameter in intradermal test with one TU PPD-RT23 are deviations from previous reports. Low incidence of cough (43.5%), marked weight loss (100%) and fever (100%) were the cardinal clinical features. TB infection on pattern suggestive of reactivation of dormant pulmonary lesions lower rate (11%) of treatment failure and infection caused by organisms other than Mycobacterium tuberculosis were other findings of the study. Importance of serosurveillance to unearth more TB cases amongst HIV infected cases for early treatment and isoniazid prophylaxis is stressed upon.     

HIV transmission through breastfeeding: a study in Malawi.

CONTEXT: Understanding the risk of human immunodeficiency virus (HIV) transmission through breastfeeding is essential for advising HIV-infected mothers and formulating public health policy recommendations. OBJECTIVE: To measure the frequency, timing, and risk factors of HIV transmission through breast milk. DESIGN: Prospective cohort study conducted between 1994 and 1997, with follow-up of infants through 24 months of age. SETTING: Postnatal clinic of tertiary care hospital, Blantyre, Malawi. PARTICIPANTS: A total of 672 infants (HIV-negative at birth) born to HIV-infected women who had not received antiretroviral drugs during or after pregnancy. MAIN OUTCOME MEASURE: Incidence of HIV in breastfed infants by age and maternal and infant risk factors for HIV transmission, using proportional hazard models to derive risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: Forty-seven children became HIV-infected while breastfeeding but none after breastfeeding had stopped. The cumulative infection rate while breastfeeding, from month 1 to the end of months 5, 11,17, and 23, was 3.5%, 7.0%, 8.9%, and 10.3%, respectively. Incidence per month was 0.7% during age 1 to 5 months, 0.6% during age 6 to 11 months, and 0.3% during age 12 to 17 months (P = .01 for trend). The only factors significantly associated with low risk of postnatal HIV transmission in a multivariate model were high maternal parity (RR, 0.23; 95% CI, 0.09-0.56) and older maternal age (RR, 0.44; 95% CI, 0.23-0.84). CONCLUSIONS: Our data suggest that the risk of HIV infection is highest in the early months of breastfeeding, which should be considered in formulating breastfeeding policy recommendations.     

Features associated with underlying HIV infection in severe acute childhood malnutrition: a cross sectional study

Introduction

Up to half of all children presenting to Nutrition Rehabilitation Units (NRUs) in Malawi with severe acute malnutrition (SAM) are infected with HIV. There are many-similarities in the clinical presentation of SAM and HIV. It is important to identify HIV infected children, in order to improve case management. This study aims to identify features suggestive of HIV in children with SAM.

Methods

All 1024 children admitted to the Blantyre NRU between July 2006 and March 2007 had demographic, anthropometric and clinical characteristics documented on admission. HIV status was known for 904 children, with 445 (43%) seropositive and 459 (45%) seronegative. Features associated with HIV were determined.

Results

Associations were found for the following signs: chronic ear discharge (OR 14.6, 95%CI 5.8–36.7), lymphadenopathy (6.4, 3.5–11.7), clubbing (4.9, 2.6–9.4), marasmus (4.9, 3.56.8), hepato-splenomegally (3.2, 1.8–5.6), and oral Candida (2.4, 1.8–3.27). Any one of these signs was present in 74% of the HIV seropositive, and 38% of HIV uninfected children. A history of recurrent respiratory infection (OR 9.6, 4.8–18.6), persistent fever, recent outpatient attendance, or hospital admission were also associated with HIV. Persistent diarrhoea was no more frequent in HIV (OR 1.1). Orphaning (OR 2.1,1.4–3.3) or a household contact with TB (OR 1.7,1.1–2.6), were more common in HIV. Each of these features were present in > 10% of seropositive children. HIV infected children were more stunted, wasted, and anaemic than uninfected children.

Conclusions

Features commonly associated with HIV were often present in uninfected children with SAM, and HIV could neither be diagnosed, nor excluded using these. We recommend HIV testing be offered to all children with SAM where HIV is prevalent.     

197例结核病患者检测HIV1+2型抗体结果分析

目的了解197例结核病患者中结核病/艾滋病(TB/HIV)双重感染情况,提高对TB/HIV双重感染检测工作的重视。方法对确诊登记的结核病人进行HIV抗体检测。结果在197例结核病患者中未发现HIV抗体检测阳性者。结论同仁地区是HIV感染的底流行地区,但TB/HIV双重感染控制工作非常严峻,开展这项工作意义重大,积累检测经验,发现TB/HIV双重感染者,降低TB/HIV双重感染的发病率和死亡率。     

核酸检测与抗体检测在艾滋病诊断中的价值

目的 探讨核酸检测、抗体检测在艾滋病诊断中的临床价值。方法 回顾性分析2017 年4 月～2019 年4 月我市收集的100 例艾滋病患者的完整临床资料,100 例患者均接受过抗体检测、核酸检测,对比分析核酸检测、抗体检测诊断早期、中晚期艾滋病感染者的诊断符合率及灵敏度。结果 经核酸、抗体检测,核酸检测早期艾滋病感染者的诊断符合率（93.33%）高于抗体检测（75.00%）;抗体检测诊断中晚期艾滋病感染者的诊断符合率（97.50%）高于核酸检测（75.00%）;核酸检测诊断早期艾滋病感染者的灵敏度（96.55%）高于抗体检测（80.36%）;抗体检测诊断中晚期艾滋病感染者的灵敏度（88.64%）高于核酸检测（71.43%）（P＜0.05）。结论 在艾滋病感染的早期诊断中,核酸检测早期艾滋病感染者的准确率、灵敏度均较高,而在艾滋病感染的中晚期诊断中,抗体检测的准确率、灵敏度则均较高。因此,核酸检测与抗体检测各有优势,临床医师应依据实际情况选择适宜的检测方式,如有必要,可尝试将二者结合应用,进一步提高临床检测艾滋病感染的诊断准确性和灵敏度,帮助医师尽早确诊艾滋病,早期予以患者相应的抗病毒治疗。