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TB/HIV management: what is new? Giovanni Sotgiu and GB Migliori Session III: Treatment and clinical management Bucharest, Friday, 25 May 2012 ERS School Course on TB and M/XDR-TB: from clinical management to control and elimination
TB/HIV co-infection Special thanks to: - Prof GB Migliori and Dr Alberto Matteelli (TBPANET-funded courses of Sondalo, Italy) - Dr Matteo Zignol (WHO office, Geneva, Switzerland) for having shared their ppt materials.
TB/HIV co-infection: outline Epidemiology. TB/HIV collaborative activities: -ICF; -IPT; -ARV therapy; -HIV testing; -CPT. News from the scientific literature: -TB/HIV co-infection and IGRA testing; -TB/HIV co-infection and LAM urine assay.
Epidemiology Cases Deaths HIV-associated TB 1.1 million (13%) (range, 1.0–1.2 million) 0.4 million (range, 0.32–0.39 million) Global burden of TB/HIV in 2010 WHO. Global TB report 2011
Epidemiology Post-primary TB Primary TB M. tuberculosis First Infection Latent TB Re-infection (exogenous) Reactivation (endogenous) Progressive Primary TB HIV positive Relative risk for TB: HIV neg. = < 10% per lifetime HIV pos. ~ 3-7 % per year
Epidemiology Incidence of TB, 2010 Prevalence of HIV among new TB patients, 2010
Epidemiology Treatment outcomes for HIV-positive and HIV-negative TB patients, 2009. WHO. Global TB report 2011 Only 21% of the estimated global HIV-related TB cases (81 countries) HIV-pos 72% VS. HIV-neg 88%
Epidemiology Treatment outcomes for HIV-positive and HIV-negative TB patients, 2009. WHO. Global TB report 2011 HIV-pos 20% VS. HIV-neg 3%
Epidemiology 41 high TB/HIV burden countries, 2010 WHO. Global TB report 2011
Kruijshaar ME et al.Eur Respir J 2011; 38. Survey on TB/HIV co-infection in EU/EEA member states
Epidemiology Kruijshaar ME et al.Eur Respir J 2011; 38. Collection of HIV status in TB surveillance systems in EU/EEA member states
Epidemiology Kruijshaar ME et al.Eur Respir J 2011; 38. Policies of HIV testing in EU/EEA member states
Epidemiology Kruijshaar ME et al.Eur Respir J 2011; 38. TB/HIV co-infected patients in EU/EEA member states
Epidemiology Kruijshaar ME et al.Eur Respir J 2011; 38. Proportion of TB/HIV patients reported to the national surveillance systems is actually suboptimal (high variability in the EU/EEA). Main obstacles: a) patient confidentiality; b) anonymous testing of HIV pts. The majority of the member states recommend testing all TB pts for HIV.
Kruijshaar ME et al.Eur Respir J 2011; 38. Systematic review of peer reviewed MS and‘‘grey literature’’ focused on TB–HIV co-infection prevalence and risk factors in EU/EEA.
Epidemiology Pimpin L et al.Eur Respir J 2011; 38. TB/HIV co-infection in EU/EEA member states
Epidemiology Pimpin L et al.Eur Respir J 2011; 38. Trends of TB/HIV co-infection in EU/EEA member states
Epidemiology Pimpin L et al.Eur Respir J 2011; 38. Socio-demographic characteristics of TB/HIV co-infected vs TB pts in EU/EEA
Epidemiology Kruijshaar ME et al.Eur Respir J 2011; 38. Males, young adults, migrants, those living in urban areas, IVDUs, homeless and prisoners identified as high-risk groups for TB–HIV coinfection.
20042012 WHO TB/HIV policy: from Interim to Definite TB/HIV collaborative activities
The Stop TB Strategy at a glance Raviglione MC et al.Lancet 2006; 367.
TB/HIV collaborative activities WHO. Policy on Collaborative TB/HIV Activities. 2012. B. Decrease the burden of TB in PLHIV through earlier ART and Three Is for HIV/TB 5. Intensify TB case finding and ensure quality TB treatment 6. Introduce TB prevention with IPT and ART 7. Infection control for TB in health care and congregate settings ensured A. Establish the mechanisms for integrated TB and HIV services 1. Set up or strengthen a TB/HIV coordinating body effective at all levels 2. Conduct HIV and TB surveillance among TB and HIV patients respectively 3. Carry out joint TB/HIV planning 4. Conduct monitoring and evaluation C. Decrease the burden of HIV in patients with presumptive and diagnosed TB 8. Provide HIV testing & counselling to patients with presumptive and diagnosed TB 9. Introduce HIV preventive methods patients with presumptive and diagnosed TB 10. Provide CPT for TB patients living with HIV 11. Ensure HIV prevention, treatment & care for TB patients living with HIV 12. Provide Antiretroviral therapy to TB patients living with HIV
Some progress in HIV care for people with TB, with more TB patients being HIV tested, although too few receive ARTs and co-trimoxazole prophylaxis Less progress on the "3Is": intensified case finding in community and facilities; infection control; and isoniazid preventive therapy
TB/HIV collaborative activities Some progress in HIV care for people with TB, with more TB patients being HIV tested, although too few receive ARTs and co-trimoxazole prophylaxis Less progress on the "3Is": intensified case finding in community and facilities; infection control; and isoniazid preventive therapy
TB/HIV collaborative activities 1.Intensified case finding in the community (door-to-door, mobile vans) and in health facilities using modern technology. 2.Infection control in health facilities: facility-level and administrative measures, environmental and personal protection. 3.Isoniazid preventive therapy, irrespective of degree of immune suppression and TST, but after careful screening to rule out active TB.
TB/HIV collaborative activities Intensified case finding (ICF) Screening and diagnosing TB in people living with HIV can be challenging. ICF is a gatekeeper for the other 2 I’s: it rapidly identifyies TB suspects (allowing triage and other measures to reduce transmission) and allows provision of IPT to PLWHA who don’t have active TB.
TB/HIV collaborative activities Intensified case finding (ICF) Adults and adolescents living with HIV should be screened with a clinical algorithm and those who reported one of the following: – current cough, – fever, – weight loss or – night sweats may have active TB and should be evaluated for TB and other diseases. WHO. IPT/ ICF recommendations. 2011
TB/HIV collaborative activities Intensified case finding (ICF) Getahun H et al. Plos Med 2011; 8. Presence of symptoms – work up for TB – Sensitivity 79% – Specificity 56% Absence of symptoms – proceed with INH preventive therapy – Negative predictive value 97% (*) – (*) at a prevalence of TB of 5%
TB/HIV collaborative activities Intensified case finding (ICF) Getahun H et al. Plos Med 2011; 8.
TB/HIV collaborative activities Intensified case finding (ICF) The addition of abnormal findings on chest X-ray increases the sensitivity from 79% to 91%, but the negative predictive value only increases from 97.8% to 98.7%. The benefits of radiology increase with the increase of TB prevalence (significant for prevalence > 20%). WHO. IPT/ ICF recommendations. 2011
TB/HIV collaborative activities Isoniazid Preventive Therapy (IPT) Akolo C et al. Cochrane Review 2010. Incidence of TB
TB/HIV collaborative activities Isoniazid Preventive Therapy (IPT) Akolo C et al. Cochrane Review 2010. In areas of high prevalence of TB (>30% infected): All HIV infected individuals who are not affected by active TB In areas of lower prevalence of TB (<30% infected): HIV infected individuals with a positive PPD test who are not affected by active TB Independently from CD4 cell count
TB/HIV collaborative activities Isoniazid Preventive Therapy (IPT) Balcells M et al. EID 2006.
TB/HIV collaborative activities Isoniazid Preventive Therapy (IPT) Samandari et al., CROI Conference, San Francisco, 2010
TB/HIV collaborative activities Isoniazid Preventive Therapy (IPT) Martinson NA, N Engl J Med 2011, 365 rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, isoniazid (300 mg) daily for up to 6 years (continuous isoniazid), isoniazid (300 mg) daily for 6 months (control group)
TB/HIV collaborative activities Isoniazid Preventive Therapy (IPT) Golub et al., AIDS 2007;21 Exposure category Person- Years TB Cases Incidence Rate (per 100 PYs) Percent Reduction (95% CI) No Rx 3,8651554.01 (3.40-4.69)- ART only 11,6272211.90 (1.66-2.17)52% (41-61%) IPT only 39551.27 (0.41-2.95)68% (24-90%) Both 1,253100.80 (0.38-1.47)80% (9-91%) Total 17,1403912.28 (2.06-2.52)
TB/HIV collaborative activities Isoniazid Preventive Therapy (IPT) Golub et al, AIDS 2009;23 Exposure category Person -years TB cases Incidence rate (per 100 PYs) (95% CI) Incidence rate ratio (95% CI) Adjusted hazard ratio* (95% CI) Naïve28152007.1 (6.2-8.2)REF HAART only 952444.6 (3.4-6.2)0.65 (0.46-0.91)0.36 (0.25-0.51) INH only427225.2 (3.4-7.8)0.73 (0.44-1.13)0.87 (0.55-1.36) Both9311.1 (0.2-7.6)0.15 (0.01-0.85)0.11 (0.02-0.78) TOTAL42872676.2 (5.5-7.0) * Adjusted for age, sex, CD4, prior history of TB, urban/rural South African Adults with HIV Infection
TB/HIV collaborative activities Isoniazid Preventive Therapy (IPT) There is no study on the threshold of resistance which make IPT non more cost effective. Even with 50% resistance there will be 50% of the subjects who will benefit from IPT. IPT recommended in Eastern Europe and Central Asia, where INH resistance is highest. TB/HIV Working Group of the Partnership Focus on European Region, Almaty, May 2010
TB/HIV collaborative activities Anti-HIV therapy HAART reduces the incidence of TB by approximately 80% in high and low burden countries. HAART reduces by >50% the rate of recurrent TB after completion of TB treatment. HAART may be key to control MDR epidemics among HIV infected persons. HAART may unmask TB in persons with low CD4 cell count. TB incidence in HIV infected persons receiving effective HAART is ~ 10 times higher than that in the background population.
TB/HIV collaborative activities Incidence of TB after initiation of HAART During the initial months of HAART incident TB cases may arise as a consequence of “unmasking” of previously subclinical disease or the deterioration of a pre-existing disease due to the reconstitution of the immune system ( Lawn, 2005 ) Dembele M, Int J Tub Lung Dis 2010, 14
TB/HIV collaborative activities Anti-TB treatment aDaily TB treatment is recommended in HIV-positive persons. bDirect observation of drug intake is recommended during the entire course of therapy, but particularly during the initial phase of treatment. cStreptomycin may be used instead of ethambutol. In meningeal TB, ethambutol should be replaced by streptomycin, which diffuses more in the meninges. dWhenever possible, drug sensitivity testing should be done to design standardized or individualized treatment regimen.
TB/HIV collaborative activities Anti-HIV therapy Decrease morbidity and mortality related to HIV/AIDS WHO recommendation Start ART in all HIV infected individuals with active tuberculosis irrespective of CD4 cell count (strong recommendation – Low quality of evidence) WHO, 2010: ART guidelines
TB/HIV collaborative activities Anti-HIV therapy Blanc FX, NEJM 2011; 365 Mortality significantly reduced in early ART group (18% - 59/332), as compared with the later-ART group (27%, 90/329) (HR, 0.62; 95% CI; 0.44 to 0.86; P = 0.006). Early (2 weeks) vs. late (8 weeks) initiation of HAART: the CAMELIA study.
TB/HIV collaborative activities Anti-HIV therapy Abdool Karim SS, NEJM 2011; 365 Timing of HIV therapy in 429 TB patients with CD4<500 in South Africa. Earlier=< 4 wks, Later=8-12 wks (not statistically significant for TB and death)
TB/HIV collaborative activities Anti-HIV therapy The STRIDE and SAPIT trials found similar results of reduced deaths and AIDS-related events with combined and earlier ART and anti-TB treatment, by 42% and 68% respectively, especially among people with a CD4 count less than 50 cells/mm 3 Havlir D et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365(16):1482-91. Abdool Karim SN et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365(16):1492-501 WHO. IPT/ ICF recommendations. 2011
TB/HIV collaborative activities Anti-HIV therapy ART should be started within 2 weeks from TB therapy in TB/HIV patients with CD4 < 50 ART can be delayed up to the end of the intensive phase of TB treatment in TB/HIV patients with CD4>50 (halved the risk of IRIS) What if CD4 cannot be measured – or timely measured? Unclear at this time
TB/HIV collaborative activities Anti-HIV therapy_IRIS (A) Antecedent requirements Diagnosis of tuberculosis before starting ART Initial response (stabilised or improved) to tuberculosis treatment (B) Clinical criteria Onset of manifestations within 3 months of ART Plus at least one major or two minor criteria Major criteria 1) New or enlarging lymph nodes, or similar cold abscesses, 2) New or worsening radiological features of TB; 3) New or worsening CNS TB; 4) New or worsening serositis Minor criteria 1) New or worsening constitutional symptoms; 2) New or worsening respiratory symptoms; 3) New or worsening abdominal pain ( C) Alternative explanations for clinical deterioration must be excluded if possible Failure of tuberculosis treatment because of tuberculosis drug resistance Poor adherence to tuberculosis treatment Another opportunistic infection or neoplasm Drug toxicity or reaction Meintjes G et al. Lancet ID 2008
TB/HIV collaborative activities Anti-HIV therapy_IRIS Make certain of diagnosis Rule out MDR TB or new opportunistic infection TB treatment should be continued ARV treatment should be continued Surgical drainage Non-steroidal anti-inflammatory drugs Steroids – 1.5 mg/kg prednisone
TB/HIV collaborative activities Anti-HIV therapy First choice: standard TB regimen + 2NRTI + Efavirenz Is a first line option for HIV treatment Is the most widely used first line regimen in resource limited settings Allows for standard TB therapy Allows for once a day therapy with minimal pill burden (Atripla)
TB/HIV collaborative activities Anti-HIV therapy_alternatives to EFV
TB/HIV collaborative activities Anti-HIV therapy_alternatives to EFV Enfuvirtide: no interactions, but parenteral NNRTIs Rifampicin decreases Etravirin exposure “significantly”. Combination not recommended CCR5 Inhibitors Rifampicin reduces maraviroc exposure by 63%. Maraviroc doses could theoretically be doubled but no clinical experience Integrase inhibitors Rifampicin reduces raltegravir exposure by 40-60%. Raltegravir 800 mg BID suggested, but optimal concentration range of this drug is unknown
TB/HIV collaborative activities Anti-HIV therapy_alternatives to EFV Rifabutin can be used with LOPINAVIR, ATAZANAVIR, FOSAMPRENAVIR, DARUNAVIR, TIPRANAVIR always with RITONAVIR boosting RIFABUTIN acceptable substitute for rifampicin, in standard TB regimens but: - not widely available - requires loose drugs
TB/HIV collaborative activities Anti-HIV therapy_alternatives to EFV Triple nuke regimens (zidovudine, lamivuine and abacavir) should be used only if no alternative regimen is available The potency (in virological terms) of this option is significantly reduced
TB/HIV collaborative activities HIV testing in TB pts (2003-2010) * The numbers under each year show the number of countries reporting data on HIV testing followed by the percentage of total estimated HIV positive TB cases accounted for by reporting countries The number of notified new and retreatment cases is shown in blue and the number of cases for which the HIV status was recorded in the TB register is shown in green. The percentage of notified TB cases with known HIV status is indicated above the green bars * WHO Global Report, 2011
TB/HIV collaborative activities HIV testing in TB pts WHO Global Report, 2011
TB/HIV collaborative activities HIV testing in TB pts Client initiated Voluntary counselling and testing (VCT) Provider-initiated Routine offer of HIV testing by health care providers Diagnostic HIV testing Mandatory testing
TB/HIV collaborative activities HIV testing in TB pts (3 C’s Principles) I.confidential. II. accompanied by counselling. III.only be conducted with informed consent, i.e. both informed and voluntary.
TB/HIV collaborative activities CPT Co-trimoxazole prophylaxis is a simple, well-tolerated and cost- effective intervention for people living with HIV. It should be implemented as an integral component of the HIV chronic care package and as a key element of pre–antiretroviral therapy care. Co-trimoxazole prophylaxis needs to continue after antiretroviral therapy is initiated until there is evidence of immune recovery. One double-strength tablet or two single-strength tablets once daily: the total daily dose is 960 mg (800 mg sulfamethoxazole + 160 mg trimethoprim).
TB/HIV collaborative activities CPT Target PopulationRecommendations HIV-infected adults and adolescents CD4 testing not available (clinical assessment only) Do not discontinue CTX prophylaxis, particularly in settings where bacterial infections and malaria are common HIV-related events [A-IV]. Consider discontinuation of CTX prophylaxis in those with evidence of good clinical response to ART (absence of clinical symptoms after at least one year of therapy), good adherence and secure access to ART. [C- IV] CD4 testing available (clinical and immunologic assessment) In countries where CTX prophylaxis is recommended only for prevention of PCP and toxoplasmosis, it can be discontinued in those with evidence of immune recovery on ART (CD4 ≥ 200/mm 3 at least 6 months on ART). [B-I] In countries with high incidence of bacterial infections and malaria, discontinue CTX prophylaxis in those with evidence of immune recovery related to ART (CD4 ≥ 350/mm 3 at least 6 months on ART). [C-IV]
TB/HIV collaborative activities CPT Globally, the number of TB patients living with HIV who were enrolled on CPT levelled off between 2009 and 2010, at just over 0.3 million. This was equivalent to 77% of TB patients known to be HIV-positive WHO Global Report, 2011
Diagnosis_IGRA Elzi L et al.BMC ID 2011; 11. To evaluate the sensitivity of T-SPOT.TB vs. TST to identify HIV+ pts with LTBI (Swiss HIV Cohort Study). 242 HIV+ pts developed culture-confirmed TB between 1993 and 2005. 64 pts had viable lymphocytes collected prior to TB diagnosis (within 6 months).
Diagnosis_IGRA Elzi L et al.BMC ID 2011; 11. T-SPOT.TB assay resulted positive in 25 (39%), negative in 18 (28%) and indeterminate in 21 (33%). T-SPOT.TB sensitivity: 39% (95% CI: 27-51%) including all results, 58% (95% CI: 43-74%) if indeterminate results are excluded. TST resulted positive in 22/44; TST sensitivity: 50% (95% CI: 35- 65%).
Diagnosis_IGRA Elzi L et al.BMC ID 2011; 11. Factors associated with a positive T-SPOT.TB
Diagnosis_IGRA Elzi L et al.BMC ID 2011; 11. Factors associated with a negative T-SPOT.TB
Diagnosis_IGRA Elzi L et al.BMC ID 2011; 11. Results of T-SPOT.TB assay according to (A) CD4 and (B) CD8 cell count
Diagnosis_IGRA Elzi L et al.BMC ID 2011; 11. Proportion of positive test results of TST and T-SPOT.TB and indeterminate TSPOT. TB results according to CD4 cell count
Diagnosis_IGRA Elzi L et al.BMC ID 2011; 11. T-SPOT.TB and TST have similar sensitivity to detect LTBI in HIV+ pts. Combination of TST and T-SPOT.TB with at least one test positive significantly increased sensitivity.
Diagnosis_LAM Minion J et al.Eur Respir J 2011; 38. Lipoarabinomannan (LAM) is a glycolipid located in the cell wall of Mtb. Urinary samples are simple to collect (particularly in children), process and store. Fewer infection control concerns.
Diagnosis_LAM Minion J et al.Eur Respir J 2011; 38. Forest plot of studies contributing to sensitivity
Diagnosis_LAM Minion J et al.Eur Respir J 2011; 38. Forest plot of studies contributing to specificity
Diagnosis_LAM #: analysis excludes pts microbiologically negative, but with strong clinical/radiological suspicion for TB; +: analysis groups the previous category with all other patients microbiologically negative to be reference negative; ƒ: analysis groups the first category with patients microbiologically positive as reference positive. Minion J et al.Eur Respir J 2011; 38. Pooled meta-analysis estimates
Diagnosis_LAM Minion J et al.Eur Respir J 2011; 38. Linear regression of sensitivity on the proportion of HIV-positive pts
Diagnosis_LAM Minion J et al.Eur Respir J 2011; 38. Proportion of specimens LAM+, by clinical status
Diagnosis_LAM Minion J et al.Eur Respir J 2011; 38. Diagnostic accuracy, by CD4 cell counts
Diagnosis_LAM Minion J et al.Eur Respir J 2011; 38. LAM urine assay is a potentially useful rule-in TB diagnostic. Inadequate sensitivity in unselected cohorts. The assay performs better in HIV+ (mainly in those with low CD4 cell counts). Even in HIV+ pts the sensitivity is suboptimal.
Alerts All TB patients, regardless of their perceived risk of HIV infection, should be offered an HIV test (increased no. of co-infected pts). In HIV infected patients clinical features of TB can be unusual. Multidisciplinary team: respiratory medicine and infectious diseases specialists.