TB, HIV and COVID-19 diagnostics and clinical management
Even though data are scarce, the analysis indicated that COVID-19/HIV/TB or COVID-19/TB co-infections may have poor treatment outcomes. This may be worsened in case TB is not diagnosed and treated early. Furthermore, COVID-19 can shadow TB in HIV-infected people or vice versa. For this reason, we suggest screening for both COVID-19 and TB in HIV-infected people with COVID-19 / TB symptoms during the COVID-19 pandemic in countries with high HIV / TB burden. HIV / COVID-19 co-infection requires a simple algorithm and management to boost TB outcomes.
5.1. TB diagnostic in COVID-19/HIV co-infection
Suspected cases of COVID-19 and TB show similar fever and/or respiratory symptoms (difficult respiration, coughing, chest pain, etc.). COVID-19 RT-PCR should be done in real-time for differential diagnosis of cases with unknown respiratory syndromes such as PTB [33]. Due to poor outcomes among COVID-19/HIV/TB or COVID-19/TB co-infections, we recommend COVID-19 real-time RT-PCR should be coupled with Xpert MTB/RIF assay. In suspected HIV/TB co-infected patients, Xpert MTB/RIF should be used first rather than traditional microscopy, culture and drug susceptibility testing (DST) [33]. Instead of collecting upper respiratory tract specimens, lower respiratory tract specimens, such as sputum, bronchoalveolar lavage, and tracheal aspirates should be collected in suspected COVID-19/HIV/TB or COVID-19/TB co-infected patients. COVID-19 real-time RT-PCR may last at least 24 hours. At the same time, the Xpert MTB / RIF assay detects M. tuberculosis and rifampicin resistance within less than two hours [34]. Xpert MTB/RIF is also a major advance in the diagnosis of TB, particularly for multidrug-resistant (MDR) TB and HIV-associated TB [34]. The Xpert MTB/RIF assay simultaneously detects M. tuberculosis and rifampicin resistance in less than two hours [34]. Furthermore, Xpert MTB/RIF is a major advance for TB diagnostic; especially for MDR-TB and HIV/TB co-infection [34]. The Xpert MTB / RIF assay’s sensitivity to detect TB is superior to that of microscopy and comparable to that of solid culture, along with high specificity [35].
This is important to emphasize that possible causes of false negative COVID-19 real-time RT-PCR results in COVID-19/HIV co-infection may be identified in patients on protease inhibitors (PIs) based regimens. We also recommend systematic TB screening in COVID-19/HIV co-infection. The adapted algorithms to diagnose TB in confirmed COVID-19/HIV co-infected adults in high burden HIV/TB countries are described below:
Option 1: This algorithm includes an interrogatory about cough of any duration, fever, short breathing, sore throat, loss of weight, loss of appetite, nausea, hemoptysis and night sweat. Past medical history includes previously confirmed TB, previous TB contact, TB preventive therapies, HIV viral load and CD4 count. Xpert MTB/RIF assay should be indicated. If Xpert MTB/RIF assay is positive, start anti TB drugs.
Option 2: This algorithm includes symptoms and medical history of COVID-19, HIV and TB as described in option 1. Xpert MTB/RIF assay should be indicated. If Xpert MTB/RIF assay is negative, the culture associated with the chest X-ray should be requested. If abnormal chest X-ray suggestive of TB, start anti-TB drugs, in the meantime while waiting for culture results.
Option 3: This algorithm includes symptoms and medical history of COVID-19, HIV and TB as described in option 1. If Xpert MTB/RIF assay is negative and the X-ray is not suggestive of TB, the culture associated with an approved interferon-gamma release assays (IGRAs) should be performed. Current evidence indicates that IGRAs perform similarly to the tuberculin skin test (TST) at identifying HIV-infected individuals with TB [36]. However, the decision to use either test should be based on country guidelines and resource and logistical considerations. If IGRAs is positive, start anti TB drugs, in the meantime while waiting for culture results.
Option 4: This algorithm includes a history of previous COVID-19, previous contact or active TB, HIV positive, HIV viral load and CD4 count. All people with cough of any duration, fever, short breathing, sore throat, weight loss, hemoptysis, night sweat, arthralgia or myalgia should be investigated for TB. Xpert MTB/RIF assay coupled with COVID-19 IgG/IgM should be indicated. A recent study has found that the specificities of serum IgM and IgG to diagnose COVID-19 were both more than 90% when compared to molecular detection [37]. If the Xpert MTB/RIF assay is negative, see options 2 and 3.
5.2. Clinical management
5.2.1. Drug-drug interactions and clinical considerations
In the case of concurrent HIV and tuberculosis infection plus SARS-CoV-2 infection, additional drug might cause interaction complicating the integrated therapy. In fact, some pharmaceutical interventions found for COVID-19 treatment including Protease inhibitors (PIs) ( atazanavir, lopinavir, ritonavir, duranavir, raltegravir,cobicistat), remdesivir, chloroquine, hydroxychloroquine, methylprednisolone, anticoagulants and carrimycin may interfere and interact to TB and/or HIV treatments in multiple ways. Although protease inhibitors (PIs) were developed to be selective inhibitors of HIV-1 replication, they have shown inhibitory activity against a wide variety of pathogens [38], including SARS-CoV. Lopinavir / ritonavir (LPV/r) has a moderate anti-SARS-CoV-2 antiviral activity which works against the 3CL protease virus [39-40]. A recent systematic review concluded that it is unclear whether LPV/r and other ART enhance clinical outcomes in severe symptomatic disease or prevent infection in patients at high- risk of COVID-19 based on the evidence available [41], as most of the studies included were case studies and also observational studies were low of power. Drug-drug interactions between PIs and rifampicin are known in HIV/TB co-infection. Studies have demonstrated that co-administration of PIs with rifampicin reduces PIs systemic concentration to less than 75% (cytochrome P 450 induction) [42-43]. This may compromise COVID-19 treatment. Remdesivir should also not associate to rifampicin in COVID-19/TB co-infection because of strong induction [44]. A recent review has reported that Chloroquine phosphate and Hydroxychloroquine showed favorable outcomes in the recovery of COVID-19 patients [45,46,47,48-49]. Both chloroquine and hydroxychloroquine are metabolized by hepatic cytochrome P450 enzyme 2D6 (CYP2D6) [50]. The most frequently involved in drug interactions are CYP3A4 and CYP2D6 [50]. The reduction in the efficacy of chloroquine when administered in conjunction with rifampicin may be due to the inducing effect of rifampicin on multidrug resistance associated protein (MRP) and development of CYP450 [51]. Additionally, high-dose chloroquine is more toxic than lower dose [44]. This is why; studies should clarify chloroquine and hydroxychloroquine dose adjustment in COVID-19/TB co-infection. Based on the above, dose adjustments should be taken into consideration in case PIs, chloroquine, hydroxychloroquine and remdesivir are administered with rifampicin. Another option is to shift rifampicin to rifabutin or adapted TB regimens without rifampicin. In contrast, clofazimine used in MDR-TB is a strong inhibitor of PIs, known substrates [52]. Then, caution should be taken when administered with PIs. Another TB drug with in vitro effect used in COVID-19 is carrimycin. Its use in COVID-19 may mitigate active TB and biases the TB diagnostic.
A study showed an association between corticosteroid use and lower mortality in COVID-19 patients [49]. Using a glucocorticoid in the early stages of the prognosis for a brief period of time could minimize the inflammation, but longer-term use could result in the risk of HIV and/or TB activation and even lack of treatment with TB. Careful use of corticosteroids with low-to-moderate doses in short courses is advised [49]. Besides, fibrosis and extensive pulmonary pathology secondary to TB and COVID-19, as defined in the introduction, can reduce drug penetration at the lung sites. It is a significant risk factor for bad TB outcomes in the event of potential infection or reactivation of TB [53]. This may also induce MDR-TB or extensively drug-resistant tuberculosis (XDR-TB) or recurrent pneumonia. Then, special considerations should be taken into account in the clinical management of COVID-19/TB lung fibrosis. Some RCTs are currently underway evaluating the safety and effectiveness of antifibrotic therapies on COVID-19 lung fibrosis [54].
Besides, liver and kidneys toxicities related to severe and critical COVID-19 need a tailored therapeutic approaches in HIV/TB co-morbidities due to some hepatotoxicity and nephrotoxicity of some HIV/TB drugs such as streptomycin, isoniazid, rifampicin, pyrazinamide, tenofovir disoproxil, atazanavir/ritonavir, lopinavir/ritonavir as well as HIV induced nephropathy and hepatitis associated to HIV.
5.2.1. Clinical management approach
Mild to Moderate COVID-19 associated with HIV/TB co-infection: Hospitalized in a special unit named COVID-19/TB units as risk patients. Start COVID-19 antiviral drugs, start or continue anti TB drugs according to the national guidelines and continue ART. Preferred COVID-19 antivirals are oseltamivir, chloroquine or hydroxychloroquine associated to LV/r or darunavir/cobicistat and Azithromycin may be indicated [49]. Chloroquine: 1 gm PO once on Day 1, then 500 mg PO once daily for 4–7 days, Hydroxychloroquine: 800 mg PO once on Day 1, then 400 mg PO once daily for 4–7 days [44] or lopinavir 400 mg/ritonavir 100 mg PO twice [44]. All of them should be associated with Azithromycin [44]. Drugs interactions should be reviewed as described above. Initial evaluation includes a chest x-ray, complete blood count (CBC), liver transaminases, renal function, inflammatory markers such as C-reactive protein (CRP), D-dimer, and ferritin, while not part of standard care, may have prognostic value.
Severe COVID-19 associated to HIV/TB co-infection: Hospitalized in COVID-19/TB unit as high-risk patients. Drug therapy and ventilator support are milestones. Clinicians can refer to COVID-19 antiviral therapy and immune-based therapy [44]. Start COVID-19 antiviral drugs as described in mild to moderate COVID-19, add immune-based therapy, initiate or continue anti TB drugs according to national guidelines and ART should be discontinued based on drug interactions and clinical considerations as described above. Remdesivir is recommended in severe/critical COVID-19 however this cannot be administered with rifampicin [44]. Short period low-dose corticosteroid therapy is preferred over no corticosteroid therapy in HIV/TB co-infection and also the patients are in the intensive care unit [44]. Anticoagulant therapy mainly with low molecular weight heparin should be initiated early as this appears to be associated with better prognosis in severe COVID-19 patients [55]. Ventilator support, oxygen through a face mask and symptomatic therapy should be indicated. Initial evaluation includes chest x-ray/CT-scan and CBC should be indicated. Liver transaminases and renal function should be monitored regularly in consideration of COVID-19/HIV/TB drug-drug interactions and clinical considerations. Measurements of inflammatory markers, D-dimer, and ferritin are part of the management.
Critical COVID-19 associated to HIV/TB co-infection: Hospitalized in COVID-19/TB unit with ICU as high-risk patients. Infection control and testing, ventilator support, hemodynamic, and drug therapy are milestones [44]. Apply COVID-19, TB and HIV management as described in severe COVID-19. Short period low-dose corticosteroid therapy, anticoagulant therapy and norepinephrine as the first-choice vasopressor are recommended [44]. Anticoagulant therapy mainly with low molecular weight heparin appears to be associated with better prognosis in severe/critical COVID‐19 patients with markedly elevated D‐dimer [55]. There is strong evidence against the use of hydroxyethyl starches for the acute reanimation of adults with COVID‐19 in shock [56]. In adults with COVID‐19 in shock, if the peripheral oxygen saturation (SpO2) is < 92%, the review suggested starting supplemental oxygen if SpO2 is < 90% [56]. Initial evaluation includes chest x-ray/CT-scan and CBC should be indicated. Liver transaminases and renal function should be monitored regularly in consideration of COVID-19-HIV and TB drug-drug interactions and clinical considerations. Inflammatory markers, D-dimer, cardiac enzymes and ferritin monitoring should be part of the management.
Previous history of COVID-19 in HIV/TB co-infection: This group of cases should be treated as HIV/TB co-infection as described in different national guidelines. Therefore, emphasis should be put on the risk of severe lung fibrosis that may induce MDR-TB or XDR-TB. Ongoing trials are evaluating the safety and effectiveness of antifibrotic therapy in COVID-19 severe and critical patients [54]. This could be beneficial in COVID-19-HIV and TB co-infected cases due to their synergic roles in inducing pulmonary fibrosis.