TB初階課程 愛滋病毒感染者結核病的診治及管理

主題大綱 結核病合併愛滋病的流行病學 世界衛生組織的 ”3 I`s for TB/HIV” 結核病合併愛滋病的臨床表現及診斷 結核病合併愛滋病的抗結核藥物治療 治療併發症

Dual epidemic of TB/HIV HIV is a driver of the TB epidemic Kwan. Clin Microb Rev 2011;24(2):351-376. 3

Epidemiology of TB/HIV -1 At least 1/3 of the 33.3 million people living with HIV worldwide is infected with TB. Persons co-infected with TB and HIV are 20-37 times more likely to develop active TB disease than persons without HIV. There were an estimated 1.1 million HIV positive TB patients globally in 2009. Around 80% of patients live in sub-Saharan Africa. WHO HIV/TB facts 2011. http://www.who.int/entity/tb/challenges/hiv/factsheet_hivtb_2011.pdf

Epidemiology of TB/HIV -2 Tuberculosis (TB) is a leading cause of illness and death for people living with HIV About 1 in 4 of the world’s 1.7 million AIDS-related deaths in 2009 was associated with TB. Between 2011-2015: 2 million PLHIV will die of TB if we fail to act now. TB is also the most common presenting illness among people living with HIV, including those who are taking antiretroviral treatment. WHO HIV/TB facts 2011. http://www.who.int/entity/tb/challenges/hiv/factsheet_hivtb_2011.pdf

Global epidemiology of HIV-associated TB disease and mortality (2009) 9,400,000 1,700,000 37% TB case fatality rate 16% TB case fatality rate Tuberculosis (TB) is the leading cause of HIV-related deaths worldwide. Of the 1.7 million people who died from TB in 2009, 400,000 (24%) were living with HIV. Additionally in 2009 there were 9.4 million new cases of TB, of which 1.2 (13%) were among people living with HIV. The risk of developing TB is estimated to be between 20-37 times greater in people living with HIV than among those without HV infection. HIV-associated TB contributes disproportionately to TB-related deaths Although HIV-associated TB accounted for 15% of all incident TB, it contributed to 29% of deaths among incident TB cases in 2008. The estimated case-fatality rate of incident TB was more than 2-fold higher for people infected with HIV (37%) than for those without HIV (16%). Source of data: http://www.who.int/hiv/topics/tb/en/index.html 6

台灣地區感染人類免疫缺乏病毒者統計表 1984-2013/08 累積HIV cases: 25,778 累積AIDS cases: 10,741 累積HIV/AIDS deaths: 4,047 累積存活個案數: 21,731 Tuberculosis (TB) is the leading cause of HIV-related deaths worldwide. Of the 1.7 million people who died from TB in 2009, 400,000 (24%) were living with HIV. Additionally in 2009 there were 9.4 million new cases of TB, of which 1.2 (13%) were among people living with HIV. The risk of developing TB is estimated to be between 20-37 times greater in people living with HIV than among those without HV infection. HIV-associated TB contributes disproportionately to TB-related deaths Although HIV-associated TB accounted for 15% of all incident TB, it contributed to 29% of deaths among incident TB cases in 2008. The estimated case-fatality rate of incident TB was more than 2-fold higher for people infected with HIV (37%) than for those without HIV (16%). Source of data: 衛生福利部疾病管制署 7

Trend of Prevalence of HIV in new diagnosed TB cases in Taiwan TB/HIV個案數 楊靖慧.愛之關懷71期

TB/HIV協同管理與篩檢 人類免疫缺乏病毒感染正如同其他慢性疾病，影響結核病的治療過程，因此對於15-49歲的所有結核病患者，均建議進行此一常規性的檢驗。若病人不同意，應填具放棄HIV檢驗聲明書。 各級衛生主管機關應設立合作模式窗口人員，定期分析與評估HIV/TB共病的趨勢(例如某縣HIV個案人數、TB個案人數、共同感染人數及比率、TB個案HIV檢驗比率等)、合作模式執行狀況等事項。

Interactions of HIV and TB Effect of HIV on TB： Increases risk of progression to active TB HIV-/TST+:5-10% lifetime risk HIV+/TST+: 8-10% per year Atypical clinical presentations Extrapulmonary TB Effect of TB on HIV： Accelerates the progression of disease in HIV Increased HIV viral load

One-year TB Mortality, comparison of HIV-infected persons and general population in different age group Yang CH, et al. Poster Presentation at 39th Union World Conference on Lung Health Oct 2008, Paris, France.

How soon after HIV seroconversion does the Risk of TB increase? TB incidence doubled within the first year of HIV infection (adjusted RR, 2.1 [95% CI, 1.4–3.1]), with a further slight increase in HIV(+) miners for longer periods, up to 7 years. Sonnenberg P. J Infect Dis 2005; 191:150-158.

Trends in TB incidence in HIV-infected persons On HAART in the U.S. (Jan 1992 to June 1998) 7.2 cases/100 p-y (95%CI 5.1–9.3) 4.7 cases/100 p-y (95%CI 2.9–6.4) 1.9 cases/100 p-y (95%CI 0.5–3.2) Figure Trends in tuberculosis rates by antiretroviral therapy status among HIV-infected persons with CD4 T-lymphocyte counts 500 cells/L, January 1992 to June 1998. Data were standardized to the Adult/Adolescent Spectrum of HIV Disease population according to demographic, HIV risk mode, and CD4 count distributions. ART antiretroviral therapy; HAART highly active antiretroviral therapy; TB tuberculosis; PY person-years. Lines are weighted smoothed estimates. Overall, 80 cases of TB occurred among 14 457 persons in 16 032 p-y of follow-up time (5.0 cases/1000 p-y, 95% confidence interval [CI] 3.9–6.1 cases/1000p-y) from January 1996 to December 1998. Of the 80 cases, 45 occurred when no antiretroviral therapy was prescribed (7.2 cases/1000 p-y, 95%CI 5.1–9.3 cases/1000 p-y); 28 cases during non-HAART antiretroviral therapy (4.7 cases/1000 p-y, 95%CI 2.9–6.4 cases/1000 p-y), and seven during HAART therapy (1.9 cases/1000 p-y, 95%CI 0.5–3.2 cases/1000p-y). Jones 2000 Int J Tuberc Lung Dis;4:1026-31. 13

Trends in TB incidence in HIV-infected persons On HAART in Taiwan. (1995 to 1999) 54.5 cases/100 p-y 10.5 cases/100 p-y Hung CC et al.J AIDS 2000;24(4):378-385

HPTN 052：Effect of ART on HIV-1 transmission in HIV-serodiscordant couples Delayed ART (n=877) Immediate ART (n=886) P-value No of HIV infections, (%) 27 (3.1) 1 (0.1) <= 0.0001 Incidence rate ratio: 0.037 (96 % reduction) Morbidity, no(%) Extrapulmonary TB 17 (1.9) 3 (0.3) 0.0013 Incidence rate ratio: 0.176 (82% reduction) Mortality, no(%) 13 (1.5) 10 (1.1) > 0.05 1. What is the HPTN 052 study?     The HPTN 052 study is a Phase III randomized clinical trial with the primary objective of evaluating whether antiretrovirals, which are medicines currently licensed to treat HIV infection, can prevent the sexual transmission of HIV among couples in which one partner is HIV-infected and the other is not (serodiscordant couples). Additionally, the study was designed to evaluate the optimal time to begin antiretroviral therapy in order to reduce illness and death among people infected with HIV/AIDS.   2. Who funded and conducted the HPTN 052 study and when did it begin?     The study was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Led by protocol chair Myron Cohen, M.D., director of the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill, the study was conducted by the HIV Prevention Trials Network (HPTN), which is largely funded by NIAID with additional funding from the National Institute on Drug Abuse and the National Institute of Mental Health, both part of the NIH. Additional support was provided by the NIAID-funded AIDS Clinical Trials Group. The study began in April 2005. Enrollment ended in May 2010.   3. How many participants were involved in the study, and where was the study conducted?     A total of 1,763 serodiscordant couples participated in the study. Each participant was at least 18 years of age (median age of 33). The vast majority of the couples (97 percent) were heterosexual. At the time of enrollment, the HIV-infected partners (890 men, 873 women) had CD4+ T-cell counts, a key measure of immune system health, between 350 and 550 cells per cubic millimeter (mm3) within 60 days of entering the study. The median CD4 count at study entry was 436 cells/mm3. The HIV-uninfected partners tested negative for the virus within 14 days of entering the study. The study took place at 13 sites in Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, the United States and Zimbabwe.   4. What was the study’s design?     Participating couples were randomly assigned to one of two treatment arms. In the first group, the HIV-infected partners immediately began taking a combination of three antiretroviral drugs.   In the second group, the HIV-infected partners delayed taking antiretrovirals until their CD4 counts fell below 250 cells/mm3, or an AIDS-related illness as defined by World Health Organization guidelines occurred. All participants in both groups received counseling on safe sex practices, free condoms, treatment for sexually transmitted infections, frequent HIV testing and evaluation and treatment for any complications related to HIV infection.   5. Which antiretroviral drugs were used in the study?     HPTN 052 participants were given a combination three- or four-drug regimen using the following 11 HIV drugs: Didanosine (400 mg once daily) Atazanavir (300 mg once daily) Efavirenz (600 mg once daily) Lopinavir/ritonavir 800/200 mg daily (Qday) or lopinavir/ritonavir 400/100 mg twice daily (BID) Lamivudine (300 mg once daily) Emtricitabine/tenofovir disoproxil fumarate (200 mg emtricitabine/300 mg tenofovir disoproxil fumarate once daily) Stavudine (weight-dependent dosage) Ritonavir (100 mg once daily, used only to boost atazanavir) Nevirapine (200 mg taken once daily for 14 days followed by 200 mg taken twice daily) The study drugs were donated by Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline and Merck & Co., Inc.   Zidovudine/lamivudine (150 mg lamivudine/300 mg zidovudine taken orally twice daily)   Tenofovir disoproxil fumarate (300 mg once daily) 6. What is a Data and Safety Monitoring Board, and how did it monitor this study?     A data and safety monitoring board (DSMB) is an independent committee composed of clinical research experts, statisticians, ethicists, and community representatives that provides additional oversight of a clinical study. The DSMB regularly reviews data while a clinical trial is underway to ensure the safety of the participants and that any benefits shown in the study are quickly made available to all participants. A DSMB may recommend that a clinical trial, or part of a trial, be stopped or modified if there are safety concerns or if the trial objectives have been achieved or are unlikely to be achieved. A DSMB looks at analyses that are not available to the investigators. Restricting certain information to the DSMB while the trial is ongoing helps to maintain the integrity of the study. The DSMB for the HPTN 052 study met at regular intervals throughout the course of the trial to review the study data. On April 28, 2011, the DSMB met for a scheduled interim review of the study’s safety and effectiveness data.   7. What were the DSMB’s findings related to HIV transmission?     The DSMB found a total of 39 cases of HIV infection among the previously uninfected partners. Of those, 28 were linked through genetic testing to the HIV-infected partner as the source of   infection. Seven infections were not linked to the HIV-infected partner, and four infections are still undergoing analysis. Of the 28 cases of linked HIV infection that occurred, 27 infections were among the 877 couples in which the HIV-infected partner delayed antiretroviral treatment. Only one case of HIV infection occurred among the 886 couples in which the HIV-infected partner began immediate antiretroviral treatment. Restated, this means that earlier initiation of antirerovirals led to a 96 percent reduction in HIV transmission to the HIV-uninfected partner. This result was statistically significant (P≤0.0001). Based on this finding, the DSMB recommended that the study participants be notified of the results.   8. What were the DSMB’s findings related to potential benefits associated with early antiretroviral use?     There were 105 morbidity and mortality events. There was a total of 65 events in the delayed treatment arm and 40 in the immediate treatment arm. The DSMB found 17 cases of extrapulmonary tuberculosis among HIV-infected participants in the delayed treatment group compared with three cases in the immediate treatment arm. This was a statistically significant finding (P=0.0013). There were 23 deaths during the study: 10 in the immediate treatment group and 13 in the delayed treatment group, a difference that did not reach statistical significance. Overall, there was a trend towards benefit for the HIV-infected participants who started antiretroviral treatment immediately, but it did not reach the 20 percent difference between study arms required for statistical significance.   9. What do these findings mean for the study participants?     The study participants are being informed of the results. Antiretroviral therapy will be offered to all consenting HIV-infected participants in the deferred treatment arm. The study investigators will continue to follow the study participants for at least one year. Individuals who became HIV-infected during the course of the study were referred to local services for appropriate medical care and treatment.   10. One of the HPTN 052 study arms involved delaying antiretroviral treatment until CD4 counts reached or fell below 250 cells per cubic millimeter. However, in 2009, the World Health Organization (WHO) revised its guidelines for when to initiate antiretrovirals recommending treatment in HIV-infected individuals with CD4 counts less than 350 cells/mm³. Was it unethical to continue the study arm based on the WHO revisions?     When the study began enrolling in April 2005, the protocol and the in-country guidelines of the participating site were consistent with the WHO treatment guidelines (November 2003) that recommended that anyone with advanced clinical HIV disease or those with CD4+ T-cell counts less than 200 cells/mm³ begin ART. However, the WHO guidelines were revised over time, recommending first that ART be considered between 200 and 350 cells/mm³ and initiated before 200 cells/mm³ (January 2006), and then to initiate antiretrovirals in all patients who have a CD4 cell count of less than 350 cells/mm³, irrespective of clinical symptoms (November 2009) In response to the first revision, most countries quickly adopted the new guidelines, and the study team changed the protocol such that the criteria for initiating antiretrovirals in the delayed treatment arm went from less than 200 cells/mm³ to between 200 and 250 cells/mm³ and raised the entry criteria for CD4 cell count from 300 to 500 cells/mm³ to 350 to 550 cells/mm³ to maintain the integrity of the study design. However, the second revision was not readily adopted by all of the countries participating in the study, primarily due to a lack of drug supply. The study team, NIAID, and the DSMB carefully considered the same data that led to the second revision of the WHO guidelines. The DSMB concluded that no change in the study was necessary based on existing HPTN 052 data and taken into consideration the safety of the participants. Nevertheless, the study team and NIAID determined that all participants should be notified of the change in the WHO guidelines and any corresponding changes in country guidelines and reminded that they are free to leave the study at any time or to start antiretrovirals outside of the study, according to the local standard of care. This action was approved by all of the institutional review boards and ethics committees overseeing the study.   11. What other relevant research is NIAID conducting?   NIAID launched a Phase IV clinical trial in March 2011 examining the optimal time for asymptomatic HIV-infected individuals to begin antiretrovirals. The study, known as Strategic Timing of Antiretroviral Therapy (START), will enroll 4,000 HIV-infected men and women in 30 countries. The START study seeks to determine if it is better for HIV-infected individuals to begin antiretrovirals when CD4 counts are above 500 cells/mm³ compared to waiting until CD4 counts fall below 350 cells/mm³.   12. What is the current state of the HIV/AIDS epidemic?   HIV/AIDS continues to be a significant global public health problem. Worldwide, 2.6 million people became newly infected with HIV in 2009 alone, and 1.8 million people died of AIDS-related disease, bringing the total number of AIDS deaths to about 30 million since the beginning of the pandemic. Here in the United States, more than 56,000 people become infected with HIV each year. In all, about 600,000 people with AIDS in this country have died. http://www.niaid.nih.gov/news/QA/Pages/HPTN052qa.aspx 15

ART reduced TB incidence in HIV-infected persons, but remains higher than the general population Location Period TB incidence in HIV(+) persons without ART Effect of ART on reduction of TB incidence in HIV(+) Residual risk compared to the general population South Africa1 2002 9.7 per 100 PY 2.4 per 100Y 5-fold South Africa2 2003 -2007 6.2 per 100 PY 4.6 per 100 PY 10-fold Brazil3 2006 2.28 per 100 PY 1.9 per 100 PY 20-fold Switzerland4 1995 0.78 per 100 PY 0.22 per 100 PY Taiwan5 1995-1999 54.5 per 100 PY 10.5 per 100 PY (1) Bagri et al. Lancet 2002;359:2059-64.　(2) Golub.JE . AIDS 2009; 23:631-636. (3) Golub JE. AIDS 2007;21:1441-1448.　 (4) Ledergerber et al. JAMA 1999;282:2220-6. (5) Hung CC. J AIDS 2000;24(4):378-385

ART in TB prevention Treatment gap: Residual increased risk post-ART 5.2 million of 33.4 million HIV-infected persons are on ART (36% eligible on treatment) 9 million need ART, but have no access Residual increased risk post-ART World Health Organization brief on antiretroviral treatment (ART) in HIV and TB prevention. http://www.who.int/hiv/topics/tb/art_for_prevention_brief_jan_2011.pdf

The Three I’s for HIV/TB Key interventions to decrease the impact of TB on people living with HIV Intensified TB case finding Isoniazid preventive therapy, and Infection control for TB. http://www.who.int/hiv/topics/tb/3is/en/index.html

HIV testing for TB patients

HIV testing rate and new HIV infection identified rate among different categories Yang CH, et al. Poster presentation at 2009 49th ICAAC, abstract H-234

The rates of receiving HIV testing and positivity of HIV among TB patients stratified by age group (2004-2007) Yang CH, et al. Poster presentation at 2009 49th ICAAC, abstract H-234

臨床表現受發生結核病時的 CD4 免疫球數值影響 臨床病徵和一般人類似，主要以肺結核表現； 胸部X 光表現通常為典型的空洞或纖維化變化。 CD4 免疫球數值越低時 較高比例同時併有肺外結核的表現，包括： 肋膜積液、淋巴結病變、心包膜炎、粟粒性結核、腦膜炎、結核菌血症等。愛滋病毒感染者 胸部X 光表現通常為非典型肺結核表現，包括︰肺部浸潤(尤其是下葉)，縱膈腔淋巴結病變。 通常痰液抹片耐酸性陰性 愛滋病毒感染者發生結核病時，臨床病徵和發生結核病時的CD4 免疫球數值有關， CD4 免疫球數值越高，臨床病徵和一般人類似，主要以肺結核表現；CD4 免疫球數值越 低時，愛滋病毒感染者發生肺結核時，較高比例同時併有肺外結核的表現，包括：肋膜 積液、淋巴結病變、心包膜炎、粟粒性結核、腦膜炎、結核菌血症等。愛滋病毒感染者 發生結核病最常見的臨床症狀，包括：咳嗽超過二至三週、有痰、體重減輕等。相較於 非感染者，愛滋病毒感染者結核病發作時，較少發生咳嗽及咳血，較常出現體重減輕及 不明原因的發燒，而肺部的理學檢查與其他肺部感染並無特異性，甚至無異常發現。胸 部X 光表現通常為非典型肺結核表現，包括︰肺部浸潤(尤其是下葉)，縱膈腔淋巴結病 變，而不是典型的空洞或纖維化變化。 結核病診治指引(第五版) 第九章

肺結核可以發生在任一時期 De Cock K M et al,Tuberculosis and HIV infection in sub-Saharan Africa; JAMA, 1992 ,268

結核病合併愛滋病的臨床表現 發生結核病最常見的臨床症狀 較少發生咳嗽及咳血，較常出現體重減輕及不明原因的發燒。 包括：咳嗽超過二至三週、有痰、體重減輕等。 較少發生咳嗽及咳血，較常出現體重減輕及不明原因的發燒。 肺部的理學檢查與其他肺部感染並無特異性，甚至無異常發現。 愛滋病毒感染者發生結核病時，臨床病徵和發生結核病時的CD4 免疫球數值有關， CD4 免疫球數值越高，臨床病徵和一般人類似，主要以肺結核表現；CD4 免疫球數值越 低時，愛滋病毒感染者發生肺結核時，較高比例同時併有肺外結核的表現，包括：肋膜 積液、淋巴結病變、心包膜炎、粟粒性結核、腦膜炎、結核菌血症等。愛滋病毒感染者 發生結核病最常見的臨床症狀，包括：咳嗽超過二至三週、有痰、體重減輕等。相較於 非感染者，愛滋病毒感染者結核病發作時，較少發生咳嗽及咳血，較常出現體重減輕及 不明原因的發燒，而肺部的理學檢查與其他肺部感染並無特異性，甚至無異常發現。胸 部X 光表現通常為非典型肺結核表現，包括︰肺部浸潤(尤其是下葉)，縱膈腔淋巴結病 變，而不是典型的空洞或纖維化變化。 結核病診治指引(第五版) 第九章

Presentation of TB in HIV-infected persons Girardi et al. Eur Respir J 2004;24:11-7.

Age of HIV+ cases with culture-confirmed TB infection in Taiwan Yang CH, et al. Poster Presentation at 17th International AIDS conference, Aug 2008, Mexico City, Mexico.

結核病合併愛滋病的診斷 活動性結核感染的診斷 肺外結核應行組織切片 進行血液結核菌培養 潛伏性結核感染的診斷 結核菌培養為標準依據 至少三次痰液抹片耐酸性染色和培養 肺外結核應行組織切片 病理檢查 結核菌培養 進行血液結核菌培養 潛伏性結核感染的診斷 結核菌素皮膚測試(TST, PPD)容易假陰性 Interferon-gamma release assay (IGRA) 在CD4增加到大於200，建議再做一次。 愛滋病毒感染者發生結核病時，臨床病徵和發生結核病時的CD4 免疫球數值有關， CD4 免疫球數值越高，臨床病徵和一般人類似，主要以肺結核表現；CD4 免疫球數值越 低時，愛滋病毒感染者發生肺結核時，較高比例同時併有肺外結核的表現，包括：肋膜 積液、淋巴結病變、心包膜炎、粟粒性結核、腦膜炎、結核菌血症等。愛滋病毒感染者 發生結核病最常見的臨床症狀，包括：咳嗽超過二至三週、有痰、體重減輕等。相較於 非感染者，愛滋病毒感染者結核病發作時，較少發生咳嗽及咳血，較常出現體重減輕及 不明原因的發燒，而肺部的理學檢查與其他肺部感染並無特異性，甚至無異常發現。胸 部X 光表現通常為非典型肺結核表現，包括︰肺部浸潤(尤其是下葉)，縱膈腔淋巴結病 變，而不是典型的空洞或纖維化變化。 結核病診治指引(第五版) 第九章

HIV/TB：抗結核藥物的選擇 原則上與非愛滋病患相同，但延長治療到九個月。 仍以含有Rifampin 或 Rifabutin為主 注意和抗愛滋病毒藥物之間的交互作用 國內現有抗愛滋病毒藥物與rifamycin 類之交互作用 蛋白酶抑制劑、非核苷酸反轉錄酶抑制劑和嵌入酶抑制 　劑，會發生不等程度的藥物交互作用。 Rifampin 或rifabutin 會刺激肝臟cytochrome P450 酵素的活 　性(特別是3A4)，降低這些抗愛滋病毒藥物的血中濃度， 　可能影響抗愛滋病毒藥物的療效。 而蛋白酶抑制劑會抑制肝臟cytochrome P450 酵素的活性， 　導致rifabutin 的血中濃度升高2-4 倍之多。 結核病診治指引(第五版) 第九章

抗愛滋病毒藥物的選擇 -1 首選是abacavir/lamivudine (Kivexa)或者zidovudine/lamivudine (Combivir) 加上efavirenz。 替代藥物為abacavir/lamivudine(Kivexa) 或者zidovudine/lamivudine (Combivir)加上nevirapine。 Efavirenz 的血中濃度，雖然會被rifampin 降低20%，但是根據台大醫院的藥物動力學研究，efavirenz 的每日劑量仍然維持600 mg，不需增加為800 mg。 Nevirapine 較容易引起肝炎和皮疹，同時nevirapine(每日劑量，400 mg)的血中濃度會被rifampin 降低40-50%。 結核病診治指引(第五版) 第九章

抗愛滋病毒藥物的選擇 -2 如果病患無法耐受efavirenz或nevirapine、發生嚴重副作用，或者病毒複製的控制不理想時(定義為:在使用前述的抗愛滋病毒藥物組合規則服用四週後，血中愛滋病毒量並未下降超過10倍以上；或者，在併用藥物組合達六個月，但是病毒量依然檢測得到，高於50-200 copies/ml)，而必須將含efavirenz或nevirapine的抗病毒藥物組合更換為以蛋白酶抑制劑為主的藥物組合時，此時rifampin必須隨同更換為rifabutin。 Rifabutin的劑量仍需依據併用的抗病毒藥物適度調整。 結核病診治指引(第五版) 第九章

對於已經接受抗愛滋病毒藥物的感染者 含 efavirenz 或nevirapine 的抗愛滋病毒藥物組 　合，抗結核藥物仍以含rifamipin 的組合為主。 含蛋白酶抑制劑的抗愛滋病毒藥物組合時，抗 　結核藥物則以含rifabutin 的組合為主。 蛋白酶抑制劑轉換成efavirenz 不過，轉換之前，必須先確認病患是否曾經接受含 　非核苷酸反轉錄酶抑制劑而且治療失敗，因為如果 　曾經發生使用含非核苷酸反轉錄酶抑制劑的抗病毒 　治療失敗，病毒會產生抗藥性，並不適合轉換。 結核病診治指引(第五版) 第九章

HIV/TB: 抗結核藥物的劑量調整 Ritonavir 是很強的CYP450抑制劑，它會增高rifabutin 的血中濃度高達4 倍之多。 Kaletra [lopinavir/ritonavir] 其他的蛋白酶抑劑也會增加rifabutin 的濃度達2 倍之多 Rifabutin + Indinavir Efavirenz 會降低rifabutin 的濃度。 Rifabutin 的藥物劑量降低為原劑量的1/4，亦即150 mg 隔日服用一次。 Rifabutin 的藥物劑量必須 　降低一半，以免因濃度過　 　高增加rifabutin 相關白血 　球減少、皮疹和葡萄膜炎 　（uveitis）副作用機會。 Rifabutin 劑量增加為450 mg。 結核病診治指引(第五版) 第九章

抗愛滋病毒藥物的開始時機 SAPIT trial, South Africa Outcome CD4 count (cells/ mm3) Early ART (within 4 wks) (n=214) Late ART (4-8weeks) (n=215) Incidence Rate Ratio (IRR) Incidence of AIDS or death Any 6.9 per 100PY 7.8 per 100PY 0.89, p=0.73 < 50 8.5 per 100PY 26.3 per 100PY 0.32, p=0.06 > 50 6.6 per 100PY 4.4 per 100PY 1.51, p=0.34 Risk of IRIS 46.8 per 100PY 9.9 per 100PY 4.7, p=0.01 15.8 per 100 PY 7.2 per 100 PY 2.0, p=0.02 Results The overall incidence of AIDS or death was 6.9 per 100 person-years in the early ART group compared with 7.8 per 100 person-years in the late ART group, which was not a significant difference (incidence rate ratio [IRR] 0.89; P = 0.73). Among the 72 participants with baseline CD4 counts < 50 cells/mm3, the difference was much greater and did reach statistical significance, with AIDS or death rates of 8.5 in the early group vs 26.3 per 100 person-years in the late group (IRR 0.32 -- a 68% reduction; P = 0.06).  IRIS incidence was nearly 5 times higher in the early compared with the late ART group, 46.8 vs 9.9 per 100 person/years, respectively (IRR 4.7; P = 0.01). 3 people -- all in the early ART group -- required antiretroviral drug switches due to adverse events. Among the 357 participants with baseline CD4 counts of at least 50 cells/mm3, the incidence rates of AIDS or death were 6.6 per 100 person/years in the early ART group vs 4.4 per 100 person/years in the late ART group, not a significant difference (P = 0.34).  The difference in IRIS incidence was much smaller among these patients, but still statistically significant: 15.8 vs 7.2 per 100 person-years in the early and late ART groups, respectively (P = 0.02). Again, the early ART group had more antiretroviral drug switches due to adverse events than the late group (7 vs 1, respectively; P = 0.04). "In patients with pulmonary TB/HIV coinfection with CD4 counts < 50 cells/mm3, early ART initiation within 4 weeks of TB treatment initiation was associated with better AIDS-free survival, albeit with increased risk of IRIS," the investigators concluded. However, they added, "in patients with CD4 [counts] > 50 cells/mm3, delaying initiation of ART to the first 4 weeks of continuation phase of TB reduced the risk of IRIS and drug switches without compromising AIDS-free survival." "Those with severe immune deficiency should start antiretroviral therapy ASAP," Abdool Karim said at the press conference. But if CD4 count is greater than 50 cells/mm3, "physicians can make a judgment" about whether the benefits of early ART outweigh the risks. Investigator affiliations: Kabdol Karim. NEJM 2010;362(8):697-706

抗愛滋病毒藥物的開始時機 CD4 count Initiation of ART after starting anti-TB treatment <50 within 2 weeks (AI) Severe disease 50-200　 2-4 weeks (BI) >200　　 2-4 week (BIII) No severe disease 50-500 within 8-12 weeks (AI) > 500 within 8-12 weeks (BIII) All HIV-infected patients with diagnosed active TB should be treated with antiretroviral therapy (ART) (AI). Severe disease: 體質耗弱、貧血、營養狀況不佳或患有全身性結核(disseminated tuberculosis) The guidelines now state that all HIV-infected patients with diagnosed active tuberculosis should be treated with antiretroviral therapy. The recommended timing of antiretroviral treatment depends on a person’s CD4 count. Patients with a CD4 count of less than 200 cells per microliter of blood should start antiretroviral therapy within two to four weeks of starting tuberculosis treatment. Patients with a CD4 count of 200 to 500 cells per microliter should start antiretroviral therapy within two to four weeks or by at most eight weeks after starting tuberculosis treatment. Patients with a CD4 count of greater than 500 cells per microliter should start antiretroviral therapy within eight weeks of starting tuberculosis treatment. DHHS guidelines. Feb 12, 2013.

Treatment outcome of culture-confirmed TB in HIV-infected patients in Taiwan Yang CH, et al. Poster Presentation at 17th International AIDS conference, Aug 2008, Mexico City, Mexico.

Treatment outcome of culture-confirmed TB in HIV-infected patients in Taiwan Yang CH, et al. Poster Presentation at 17th International AIDS conference, Aug 2008, Mexico City, Mexico.

愛滋病毒感染者結核病治療的免疫重建症候群 Immune reconstitution inflammatory syndrome (IRIS) 初步達到症狀緩解的成效後，在繼續治療中可能會 　發生病症惡化，再度出現發燒、淋巴腺腫、皮膚栗 　粒性結節、腦膿瘍等；胸部X-光可能惡化。 甚至很可能還可以從臨床檢體中發現結核菌，但是 　對抗結核藥物仍然具有敏感性。 通常是在抗愛滋病毒藥物和抗結核藥物併用後的四 　到六週內發生，時序上似乎和開始使用抗愛滋病毒 　藥物有關。 併有結核病的愛滋病毒感染者規則地服用藥物，初步達到症狀緩解的成效後，有部 份的患者，在繼續治療中可能會發生病症惡化，再度出現發燒、淋巴腺腫、皮膚栗粒性 結節、腦膿瘍等；胸部X-光可能惡化，甚至很可能還可以從臨床檢體中發現結核菌，但 是這些結核菌對於使用中的抗結核藥物仍然具有敏感性。這種矛盾的反應，目前被稱為 免疫重建症候群。這種現象並不僅限於愛滋病毒感染者才會發生，不過其發生率確實高 於非愛滋病毒感染者，特別當他們同時接受抗愛滋病毒藥物時，發生機會尤其更高。矛 盾反應發生的時間，通常是在抗愛滋病毒藥物和抗結核藥物併用後的四到六週內發生， 時序上似乎和開始使用抗愛滋病毒藥物有關。因此，如前所討論，如非急迫的需要，應 先治療結核病，因為結核菌可藉飛沫傳染，而且結核病具有較高的短期內的死亡率。待 結核病治療穩定後，再開始抗愛滋病毒藥物治療。如此，可能降低免疫重建症候群的發 生機率。 結核病診治指引(第五版) 第九章

Risk Factors for TB/IRIS Starting ART within 6 weeks of TB treatment Disseminated, extra-pulmonary disease Low base line CD4 count Rise in CD4 % Fall in viral load High bacillary burden Kumarasamy N. J AIDS 2004; Lawn SD. AIDS 2007; Navas E. Arch Intern Med 2002.

Differential Diagnosis of IRIS Side Effects of ART Drug Fever TB not responding to standard anti-TB treatment Other concomitant infection Failure of HAART (late IRIS)

“Suspected TB IRIS”： a TB patient who after starting HAART develops either New persistent fevers (temperature >38.6°C) which last for more than 1 week without an identifiable source (e.g., urine and sputa testing, and other procedures when clinically indicated) or reason (e.g. an allergic reaction) or marked worsening or emergence of intrathoracic lymphadenopathy, pulmonary infiltrates or worsening or emergence of cervical adenopathies/abscesses, or worsening of other tuberculous lesions or manifestations, such as cutaneous peritoneal or central nervous system (CNS) inflammatory pathology.

“Suspected TB IRIS”: a patient who after starting HAART develops TB characterised by the formation of Large adenopathies Abscesses Miliary TB with large nodules Cavity formation

“Confirmed” TB IRIS Same definition as suspected TB IRIS but multi drug resistant TB excluded a satisfactory virological response to ART and

TB/IRIS：Treatment Recommendations Drainage Adding prednisolone/NSAIDS may be beneficial Continue HAART in most cases Consider stopping ARTs if life threatening?

ART & Isoniazid Prevention Treatment (IPT) can Reduce TB Incidence in HIV-infected persons ART: antiretroviral therapy; IPT: isoniazid preventive treatment IR: incidence rate; TB: tuberculosis: ref: reference Golub JE. AIDS 2007;21:1441-1448. Golub.JE . AIDS 2009; 23:631-636.

IPT can reduce TB incidence in HIV-infected Pts

潛伏性結核感染的治療 所有新診斷的愛滋病毒感染者： 潛伏性感染治療： 目前的臨床研究建議的處方： 建議確認是否有潛伏性結核感染。 目前可以考慮使用的方法是結核菌素皮膚試驗(TST)及 　IGRA TST陽性的定義為當硬節大於等於5 mm。 潛伏性感染治療： 陽性感染者建議接受預防性治療 最近有接觸活動性結核病患者 目前的臨床研究建議的處方： Isoniazid 每天每公斤5 mg，最多300 mg，治療9個月。 可以同時加上pyridoxine，以避免周邊神經炎。 結核病診治指引(第五版) 第九章

HIV/TB：Decreased infectiousness of TB A lower likelihood of cavitary disease A higher frequency of smear-negative pulmonary TB Extrapulmonary TB, which lower the mycobacterial load in the sputum. HIV may also decrease the mean duration of infectiousness of TB because of earlier presentation and diagnosis and shorter time to death in persons infected with HIV. Kwan CK. Clin Microbiol Rev 2011;24(2):351–376 HIV and Tuberculosis：a Deadly Human Syndemic

Summary TB is the leading cause of death in HIV- infected persons. WHO's 3 I's provide a roadmap for control 　of TB/HIV epidemic. Treating TB/HIV coinfection is a challenge 　requiring expert consultation. Drug-drug interaction & TB/IRIS One million lives can be saved between now 　and the end of 2015 by preventing and treating 　TB among people living with HIV‬.

重點回顧 結核病會加重愛滋病病程、愛滋病也會加重結核病病程。 愛滋病人的服藥順從性困難度高 注意藥物交互作用 強化都治計畫(不同族群考量) 、兩種疾病之整合 　照護。 注意藥物交互作用 觀察併發症(如免疫重建症候群…)