Abstract
The management of multidrug-resistant tuberculosis (MDR TB) is notably complex among patients with human immunodeficiency virus (HIV). TB treatment recommendations typically include very little information specific to HIV and MDR TB, which often is derived from clinical trials conducted in low-resource settings. Mortality rates among patients with HIV and MDR TB remain high. We reviewed the published literature and recommendations to synthesize possible patient management approaches demonstrated to improve treatment outcomes in high-resourced countries for patients with MDR TB and HIV. Approaches to diagnostic testing, impact and timing of antiretroviral therapy on mortality, anti–MDR TB and antiretroviral drug interactions, and the potential role for short-course MDR TB therapy are examined. The combination of antiretroviral therapy with expanded TB drug therapy, along with the management of immune reconstitution inflammatory syndrome, other potential HIV-associated opportunistic diseases, and drug toxicities, necessitate an integrated multidisciplinary patient care approach using public health case management and provider expertise in drug-resistant TB and HIV management.
Despite a relatively low incidence of tuberculosis (TB) diagnosed among patients with human immunodeficiency virus (HIV) living within the United States, TB is associated with significantly increased risk for both all-cause and acquired immunodeficiency syndrome–related death (1–6). The negative immunologic impact on T cell function conferred by HIV heightens the risk of TB disease progression. The presence of HIV significantly influences TB pathogenesis, clinical presentation, and management. Rifampin monoresistance has been identified more often in people living with HIV compared with those without HIV (7–9). A recent systemic review and meta-analysis of predominately non-U.S. patients found a marginal, but consistent, increased risk of multidrug-resistant TB (MDR TB; resistance to at least isoniazid and rifampin) occurring among patients with HIV, and more notably for primary MDR TB acquisition (10). Primary extensively drug-resistant TB (XDR TB) acquisition among patients with HIV has been described in both community and healthcare settings in South Africa (11, 12). Persons with untreated HIV, because of immunosuppression, may be particularly susceptible to acquiring Mycobacterium tuberculosis (Mtb) infection (including MDR Mtb) upon exposure in settings of poor infection control, and have been shown to rapidly progress to TB disease (13).
From 2013 through 2017 in the United States, 498 cases (1% of total reported TB cases) had MDR TB, of which 24 (5% of MDR TB cases) also had HIV (14). Despite the low percentage of patients in the United States with both MDR TB and HIV, this comorbidity remains an important public health concern. Higher rates of unsuccessful treatment outcomes, including death, occur among patients with HIV and MDR TB (15, 16). Low CD4 cell counts (e.g., 50 cells/μl or less) in patients with HIV and MDR TB correlate with higher mortality (17, 18). Current published guidelines provide only limited guidance specifically addressing the management of MDR TB in persons with HIV (19–22).
We discuss the treatment approaches for MDR TB in the context of HIV coinfection and antiretroviral therapy (ART) in high-resourced settings. Treatment recommendations for MDR TB have been recently updated by the World Health Organization (WHO) and supported through a large-scale meta-analysis of individualized patient data for the preferential inclusion of a later-generation fluoroquinolone, bedaquiline, and linezolid (19, 23). Available medical resources vary significantly among countries endemic with TB with HIV, and providers must appropriately use available diagnostic tools and local drug formularies to optimize treatment outcomes. Anticipated in the 2019–2020 are guidelines for the treatment of drug-resistant TB in well-resourced settings, from the American Thoracic Society (ATS), in collaboration with the Centers for Disease Control and Prevention (CDC), the Infectious Diseases Society of America (IDSA), and the European Respiratory Society (ERS).
Globally, only 60% of the human population with HIV is aware of their infection, and many patients learn they have HIV when diagnosed with TB. Because of the serious consequences of TB in this highly susceptible population, combined with the mortality of untreated HIV, the CDC, the European Union Standards for Tuberculosis Care, and the WHO jointly recommend HIV testing of people with suspected or confirmed TB (24–27). The WHO’s End TB Strategy further recommends universal HIV testing to reduce TB incidence and mortality (28).
Confirming a bacteriologic diagnosis of TB in patients with advanced HIV can be challenging, as the lack of sufficient immunologic response hinders pulmonary cavity formation and promotes extrapulmonary dissemination. The higher prevalence of drug-resistant TB among patients with HIV, especially among those who have lived within endemic TB regions, coupled with the increased risk of death if effective MDR TB treatment is delayed, further support the CDC recommendation for the routine adjunctive use of nucleic acid amplification tests (NAATs) to expedite a diagnosis of TB and molecular diagnostic drug susceptibility testing for rifampin (with or without isoniazid) as part of the initial diagnostic evaluation for patients with HIV and TB (29, 30). NAATs amplify specific target Mtb RNA or DNA sequences and significantly shorten the time to diagnosis compared with culture-based identification methods.
The lateral flow lipoarabinomannan (LF-LAM) assay (Alere DetermineTM TB LAM Ag; Alere Inc.) is a point-of-care urine test to rapidly detect mycobacterial cell wall LAM antigens in persons with TB disease. The WHO has endorsed its use in persons with CD4 cell counts under 100 cells/μl suspected of having TB and in those with severe TB disease at any stage of HIV (31); but the test has decreased sensitivity if CD4 counts are above 100 cells/μl, has cross-reactivity with other mycobacteria, and requires confirmatory testing by NAAT or culture (32). In addition, it has not yet been approved by the U.S. Food and Drug Administration (FDA) for use in the United States
The use of molecular diagnostic assays, such as the Xpert MTB/RIF assay (Cepheid), for both the rapid detection of Mtb and gene mutations conferring resistance to rifampin (a key drug used to treat TB), have reduced time to diagnosis, thereby enabling an earlier start of effective MDR TB therapy (33, 34). The Xpert MTB/RIF assay uses real-time PCR directly on sputum samples in an automated cartridge-based testing platform and has demonstrated a sensitivity of identifying Mtb in 98% of AFB smear positive sputum samples and 73% in smear-negative samples, as well as identifying 98% of rifampin-resistant strains (35). Among patients with HIV and pulmonary TB, the sensitivity of the Xpert MTB/RIF assay is slightly lower compared with those without HIV (93.9% vs. 98.4%; P = 0.02) (35). To improve upon the low sensitivity of Xpert in the detection of more paucibacillary, smear-negative pulmonary TB (which is more commonly seen in patient with HIV), the Xpert MTB/RIF Ultra was developed. A recent comparison of Cepheid’s Xpert MTB/RIF Ultra to Xpert MTB/RIF in eight high–TB-incident (including MDR TB) countries and in a Western European country revealed a higher overall sensitivity for Mtb detection using the Ultra assay, especially in patients with smear-negative disease or with HIV (36, 37). However, Xpert MTB/RIF Ultra has not yet been FDA approved for use in the United States.
Line probe assays incorporate reverse hybridization of microbial DNA on a paper strip and detect both the presence of Mtb DNA as well as gene mutations conferring resistance to select drugs. The INNO-LiPA RIF TB (Innogenetics) identifies resistance to rifampin, the GenoType MTBDRplus (Hain Life-Science) identifies resistance to both isoniazid and rifampin, and the GenoType MTBDRsl (Hain Life-Science) identifies resistance to the fluoroquinolones and injectable agents. The sensitivity of the GenoType MTBDRplus for Mtb detection and rifampin resistance is comparable to that of the Xpert MTB/RIF (38). In settings where whole-genome sequencing is used, the role of line probe assays for rapid detection of drug resistance and determination of effective treatment medications is still useful.
The CDC’s Division of Tuberculosis Elimination offers a service for molecular detection of drug resistance (MDDR) that identifies resistance to isoniazid, rifampin, pyrazinamide, ethambutol, the fluoroquinolones, and injectable agents directly through targeted DNA sequencing (39). Other select U.S. state and regional public health laboratories have started using sequencing-based drug resistance detection platforms for more rapid and accurate diagnosis of drug-resistant TB (40–42).
ART is a vital component toward successful MDR TB management in patients with HIV. A systematic review of 10 observational studies, including individual patient data from 217 patients with both HIV and drug-resistant TB (92% of which was MDR TB) showed that patients taking ART had higher survival and TB cure rates compared with those not taking ART (43). Although the relationship between the time of starting ART and TB mortality was not specifically evaluated, the benefit of ART was most prominently identified among patients with CD4 counts less than 50 cells/μl. An individual patient data meta-analysis that included 1,833 patients with MDR TB and HIV, of whom 906 were receiving ART, documented treatment success for 55% (95% confidence interval [CI] = 43–66%) of those receiving ART, compared with 34% (95% CI = 24–46%) of those not receiving ART; mortality was also marginally lower (26% vs. 29%), with authors stating a need to treat HIV as well as drug-resistant TB (23). A subcohort of patients with HIV with XDR TB in South Africa were prospectively followed for up to 60 months after starting TB therapy (44). Although outcomes among patients with XDR TB were generally poor, ART was a significant predictor of survival in patients with HIV and comparable to those without HIV.
Other retrospective and case–control studies within South Africa among patients with drug-resistant TB and HIV have also shown a strong favorable relationship between starting ART and decreasing patient mortality. A review of patients with XDR TB from four provincial treatment centers by Dheda and colleagues (45) revealed 41% decreased mortality at 12 months among patients with HIV receiving ART (25% mortality) compared with those not on ART (66%). In a region within rural KwuaZulu-Natal province, where over 80% of all patients with TB also have HIV, Gandhi and colleagues (17) evaluated patients with HIV and MDR or XDR TB, and found that a CD4 cell count under 50 cells/μl was a strong risk factor for mortality, whereas use of ART was correspondingly protective. In Eastern Cape Province, Kvasnovsky and colleagues (46) found that patients with XDR TB and HIV who were not taking ART had a significantly lower 12-month survival compared with patients taking ART. Within Lesotho, Satti and colleagues (47) found that, among patients with MDR TB and HIV who died, those not taking ART had a shorter median time to death. Despite the more limited treatment options, these studies within South Africa collectively support the assertion that patients with HIV and drug-resistant TB have better outcomes when taking ART.
Among patients with HIV and predominantly drug-susceptible TB evaluated in the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis), CAMELIA (Cambodian Early versus Late Introduction of Antiretrovirals), and A5221 STRIDE (An international randomized trial of immediate vs early antiretroviral therapy [ART] in HIV+ patients treated for tuberculosis) trials, starting effective ART during TB therapy has been shown to increase patient survival, with an emphasis on starting ART earlier in patients with lower CD4 cell counts (48–51). The SAPiT trial demonstrated 56% reduction in relative risk of death among patients starting ART within 12 weeks after starting TB therapy compared with those starting ART after completion of TB therapy; the survival benefit was restricted to patients with CD4 cell counts under 50 cells/μl (49, 51). Among a subgroup of patients with HIV and MDR TB in the SAPiT study in South Africa, an 86% reduction in mortality was seen among patients who started ART within 12 weeks of starting TB therapy compared with those who deferred ART until after completion of TB therapy (52). Interestingly, the survival advantage was seen even among patients receiving inappropriate TB treatment, further illustrating the importance of concurrent effective HIV care. The CAMELIA trial found significantly increased survival with ART initiation 2 weeks after the start of TB treatment among adults with CD4 cell counts of less than or equal to 200 cells/μl, compared with starting ART eight or more weeks after commencing TB treatment (48). Similar reduced mortality benefits of early ART in patients with CD4 counts under 50 cells/μl were demonstrated in the STRIDE A5221 trial (50). These trials, however, did not correlate outcomes based on TB drug resistance.
Results from these studies were influential in the updated joint CDC/ATS/IDSA and WHO TB management guidelines that recommend starting ART as soon as possible in all patients with drug susceptible TB and HIV, ideally within 2 weeks of starting TB therapy for patients with CD4 counts under 50 cells/μl and by 8–12 weeks for patients with CD4 counts of 50 cells/μl or higher (53, 54). At this time, however, no controlled studies have been performed outlining the optimal time to start ART in patients with HIV and drug-resistant TB, and such trials would most likely require a multicenter collaborative across a number of countries. Regardless of ART timing, persons with HIV on ART and with MDR TB demonstrated similar culture-conversion rates and time to negative cultures compared with those without HIV in several studies (55–57). However, longer time to culture conversion was found in two large cohort studies in nine countries (Estonia, Latvia, Peru, the Philippines, Russia, South Africa, South Korea, Taiwan, and Thailand), where only half of the patients infected with HIV received ART (58). The decreased mortality associated with starting ART in patients with drug-resistant TB, especially those with MDR and XDR TB and in patients with CD4 cell counts below 50 cells/μl, collectively suggest that a similar ART approach for persons with drug-resistant TB to that for drug-susceptible TB may be beneficial.
Clinical monitoring for immune reconstitution inflammatory syndrome (IRIS) is encouraged, as the SAPiT, CAMELIA, and A5221 STRIDE trials all showed a higher incidence of IRIS among patients starting ART earlier compared with those starting later (48–51). Diagnosing IRIS is predicated on excluding alternative etiologies, including other opportunistic infections and TB treatment failure, which can be challenging in patients with more extensive drug-resistant TB. IRIS usually does not require changes in TB drug therapy and can often be controlled with nonsteroidal antiinflammatory drugs or corticosteroids (59). Treatment of patients with confirmed TB-IRIS with corticosteroids (e.g., oral prednisone) for 1 or more months might lower incidence of IRIS complications, but is not recommended for those with Kaposi’s sarcoma. More information can be found in the Department of Health and Human Services Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents (https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/325/tb). A recent randomized clinical trial in South Africa that treated patients at increased risk of IRIS, including those with low CD4 cell counts, with prednisone during the first 4 weeks after initiation of ART demonstrated a lower incidence of IRIS compared with placebo, but was not sufficiently powered to address mortality or associated malignancies (60). Further characterization of patient mortality and associated malignancy risk by CD4 count requires further study in other settings.
Resistance to isoniazid and/or rifampin in patients with HIV with TB meningitis is associated with increased mortality (61, 62), and the early identification of drug resistance is important toward achieving a successful outcome. Although not specifically evaluating drug-resistant TB, a randomized, controlled trial in Vietnam among patients with HIV and TB meningitis found a higher frequency of severe (grade 4) adverse events and a non–statistically significant increase in death among patients starting ART within 7 days of starting TB therapy compared with those starting ART after receiving 2 months of TB treatment (63). Out of concern that early ART initiation may be detrimental in patients with TB meningitis, it has been recommended to delay starting ART in patients with drug-susceptible central nervous system (CNS) TB and HIV by 2 months after starting TB therapy (54).
The optimal timing to start ART in patients with CNS MDR TB and HIV remains unclear, as there are little published data to provide further guidance. Until more outcome data are available in patients with CNS MDR TB, a similar approach with ART used in patients with drug-susceptible CNS TB and HIV seems reasonable. Patients who develop new adverse neurologic symptoms or worsening neuroimaging findings during treatment of MDR CNS TB should be evaluated for IRIS, other opportunistic infections, select malignancies, and the potential for TB treatment failure (64). Therapeutic drug monitoring of second-line anti-TB medications may help optimize dosing and CNS penetration (65).
Drug interactions between antiretroviral and anti-TB agents are common in the management of patients with HIV and TB. Although the rifamycins are not typically used in patients with MDR and XDR TB, rifabutin is occasionally included by some authorities in select cases of discordant rifampin drug resistance and/or the presence of disputed rpoB gene mutations. Rifampin (and to a lesser degree rifapentine and rifabutin) increases the metabolic activity of the hepatic cytochrome P450 (CYP) enzymes (including CYP subfamilies 3A and 2C), P-glycoprotein, as well as uridine diphosphate glucuronosyltransferase. The specific rifamycin impact on the protease inhibitors, nonnucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors and chemokine receptor inhibitors, along with corresponding dosing recommendations, has been described in detail elsewhere (66, 67). Non-rifamycin first-line TB drugs (isoniazid, pyrazinamide, and ethambutol), the fluoroquinolones, the injectables (amikacin, kanamycin, streptomycin, and capreomycin), as well as other second- and third-line drugs (including ethionamide, cycloserine, para-aminosalicylic acid [PAS], linezolid, and meropenem) pose fewer pharmacokinetic interactions with most antiretroviral drugs. Select adverse non-rifamycin drug interactions and overlapping toxicities with ART are listed in Table 1.
| Potential Overlapping Toxicities and Drug–Drug Interactions | Antiretroviral Drugs* | Non-Rifamycin TB Drugs | Comments |
|---|---|---|---|
| Dysglycemia | Lopinavir/ritonavir (Kaletra), ritonavir, zidovudine | Ethionamide, PAS, fluoroquinolones†, linezolid | Recommend close serum glucose monitoring in patient with glucose intolerance or diabetes |
| Hepatic cytochrome P450 enzyme system metabolism | Induce CYP P450 metabolism: efavirenz, etravirine, and nevirapine | Bedaquiline, delamanid | Other medications, including over-the-counter drugs, should be thoroughly reviewed for CYP P450 metabolic interactions |
| Impede CYP P450 metabolism: protease inhibitors, cobicistat | |||
| Hepatoxicity | Lactic acidosis with hepatic steatosis higher risk with zidovudine; protease inhibitors; nevirapine (higher risk in patients with elevated CD4 cell counts); less common with efavirenz, etravirine & rilpivirine; maraviroc | Isoniazid, pyrazinamide, ethionamide, PAS, clofazimine | Serum LFT monitoring recommended in patients with HIV and TB; consider more frequent monitoring in those with underlying chronic liver disease |
| Indirect hyperbilirubinemia‡: atazanavir | |||
| Lactic acidosis | Zidovudine (see hepatoxicity above) | Linezolid | |
| Mental health changes (depression, psychosis, dizziness, etc.) | Efavirenz, rilpivirine; dolutegravir, elvitegravir, raltegravir | Cycloserine, isoniazid, ethionamide, fluoroquinolones† | Use with caution in patients with mental health conditions |
| Risk of evoking serotonin syndrome when combining linezolid with either SSRI or SNRI agents | |||
| Myelosuppression / cytopenias | Zidovudine | Linezolid | Recommend CBC monitoring with linezolid usage |
| Nephrotoxicity | Tenofovir§, atazanavir | Aminoglycosides, capreomycin | Recommend monitoring serum creatinine when an injectable agent is used. |
| Isolated creatinine elevation||: cobicistat, dolutegravir | |||
| Peripheral neuropathy | Zidovudine | Aminoglycosides, capreomycin, linezolid, isoniazid, ethionamide, cycloserine, fluoroquinolones† | Consider vitamin B6 supplementation with cycloserine, ethionamide, high-dose isoniazid, linezolid |
| QTc interval prolongation; cardiac dysrhythmia | Lopinavir/ritonavir (Kaletra), efavirenz | Fluoroquinolones†, bedaquiline, delamanid, clofazimine | Consider baseline and follow-up ECG monitoring in patients taking combination medications with QTc prolongation potential |
| Note PR interval prolongation¶ with atazanavir, lopinavir/ritonavir | |||
| Skin rash | Nevirapine (higher risk in patients with elevated CD4 cell counts), efavirenz, etravirine, rilpivirine; Any protease inhibitor (esp. those containing sulfonamide moiety: e.g., darunavir); abacavir (hypersensitive reaction a risk in patient who are HLA-B5701 positive); raltegravir | All TB drugs | Review patients other medications that commonly may cause skin rash (e.g. trimethoprim/sulfamethoxazole) |
| Note skin pigmentation with clofazimine use | |||
| Thiacetazone** is contraindicated in patients with HIV |
Antiretroviral drugs, such as efavirenz, etravirine, and nevirapine, have the potential to accelerate the metabolism and consequently decrease the exposure of rifabutin, bedaquiline, and delamanid by inducing the hepatic CYP 3A4 enzyme system. Protease inhibitors and pharmacokinetic boosting agents, such as cobicistat and ritonavir, impede drug metabolism through this this same pathway, resulting in corresponding increased serum drug concentrations of CYP3A4 substrates. A more detailed review of specific drug–drug interactions can be reviewed in Tables 17–20 of the National Institutes of Health HIV treatment guidelines, which can be found at https://aidsinfo.nih.gov.
Prolongation of the QTc interval may occur with select antiretroviral and TB drugs, and the effect can be enhanced when administered together. Bedaquiline, delamanid, clofazimine, the fluoroquinolones, as well as efavirenz and some protease inhibitors, can all contribute toward QTc interval prolongation and potential ventricular dysrhythmia. Electrolyte abnormalities including hypokalemia, hypocalcemia, and hypomagnesemia from aminoglycoside or capreomycin use may augment this effect. In addition, commonly used supportive care medications, including methadone, high-dose trimethoprim/sulfamethoxazole (e.g., treatment of Pneumocystis pneumonia), and triazoles, may also collectively contribute to QTc prolongation (68, 69). For patients receiving multiple medications with QTc-prolonging potential and for patients with other risks for cardiac dysrhythmia, baseline and follow-up electrocardiogram monitoring should be considered. There currently are no formal recommendations regarding the timing and frequency of QTc monitoring in patients with TB. Prolonged QTc intervals over 500 milliseconds or an increase in over 60 milliseconds should raise consideration for alternative drug selection (70).
Providers should also have heightened awareness for other possible overlapping drug toxicities, including nephrotoxicity in patients receiving an injectable agent and tenofovir disoproxil, adverse changes in mental health among patients taking efavirenz with cycloserine, and additive gastric intolerance among patients taking select protease inhibitors with ethionamide and/or PAS. Cation-containing drugs (e.g., antacids or supplements containing aluminum, calcium, magnesium, and iron) can bind to integrase strand transfer inhibitors and the fluoroquinolones, resulting in reduced enteric absorption. Antacids, H2 antagonists, and proton pump inhibitors can reduce the enteric absorption of medications that require gastric acidity, such as atazanavir, rilpivirine, and PAS. A full review of all medications should be performed with each patient to identify potential drug interactions and toxicities before starting MDR TB and HIV therapies.
Employing appropriate case management that includes directly observed therapy helps ensure patient adherence with a complex treatment program, identify onset of drug toxicity, and prevent treatment lapses that might pose challenges to infection control. Composing an effective, nonantagonistic combination ART and anti-TB regimen, managing drug toxicities, and assessing longitudinal patient responses require a closely integrated multidisciplinary healthcare team with expertise in drug-resistant TB, HIV, and public health. Most health providers have limited clinical experience managing patients with combined MDR TB and HIV, and available expert medical consultation can help ensure timely patient care decisions, including the identification of referral laboratories for expanded rapid molecular drug susceptibility testing and appropriate public health interventions. Expert medical consultation, education and training can be obtained from U.S. public health programs (https://www.cdc.gov/tb/links/tboffices.htm), the CDC-funded Centers of Excellence (https://www.cdc.gov/tb/education/tb_coe/default.htm), and international organizations, including the ERS-WHO Electronic Consilium and Global TB Network (71, 72).
Shorter courses of MDR TB drug therapy ranging from 9 to 12 months have been recommended by the WHO for select patients (20). Although patients with HIV are not excluded by the WHO from these shorter regimens, treatment outcome data supporting the use of shorter regimens, specifically in patients with HIV, is minimal and mainly from study sites in Africa, where laboratory capacity for drug susceptibility testing was low. A clinical observational study using a 9-month MDR TB regimen conducted in Bangladesh did not specifically evaluate treatment outcome in patients with HIV (73, 74). In Cameroon, 20% of patients evaluated with a 12-month MDR TB regimen had HIV infection with no measurable effect on treatment outcome; however, the study was not powered to determine the impact of HIV infection on outcome (75). In another observational study using a 12-month MDR TB regimen in Niger, there were not enough patients with both HIV and MDR TB to make any conclusions (76). The drug regimens in these studies included a 4-month induction period of kanamycin, isoniazid, prothionamide, gatifloxacin, clofazimine, ethambutol, and pyrazinamide, followed by another 5–8 months with the latter five drugs. They predominantly included patients who had both confirmed or suspected pulmonary MDR TB that was susceptible to the injectable and fluoroquinolone drugs used and who had not received prior therapy with non–first-line TB drugs for greater than 1 month before enrollment.
A subsequent randomized clinical trial involving patients from nine countries in West and Central Africa used a standardized 9-month regimen of moxifloxacin, clofazimine, ethambutol, and pyrazinamide that was supplemented during the first 4–6 months with kanamycin, protionamide, and isoniazid (77). Among the 20% of enrolled patients who were HIV positive, there was a higher proportion of deaths, but no difference in rates of successful outcome or bacteriologic failure based on HIV status. Fluoroquinolone drug resistance was the strongest identified risk factor for unsuccessful treatment and failure. Preliminary data from the STREAM-1 (Standard Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR TB) trial enrolling patients with MDR TB in Mongolia, Ethiopia, South Africa, and Vietnam also found a higher, but non–statistically significant, number of deaths among patients with HIV randomized to receive the same short-course treatment regimen (78).
The best use of the short-course regimens in patients with MDR TB and HIV has not yet been well defined. Until more outcome data with the shorter-course MDR TB regimens in patients with HIV are available, these shorter-course MDR TB regimens for patients with HIV should be used with caution and considered within a clinical trial setting. Given that drug susceptibility testing is more widely available within the United States, it is preferable to use drugs confirmed susceptible in vitro for such regimens.
Well-designed clinical trials involving patients with MDR TB and HIV are lacking. Many of the studies citing the impact of ART in patients with HIV and MDR TB, including short-course MDR-TB therapies, were observational and nonrandomized. There is a possible risk of biased data in studies from countries with differing MDR TB and HIV endemicity rates and medical resources. The CAMELIA, SAPiT, and STRIDE trials took place in low-resource settings, and diagnostic testing and treatment outcomes might be improved in higher-resourced locations. Because of the relatively low numbers of patients with TB and HIV in high-resource settings (14, 18), large trials focusing on the timing of ART in such settings have not been conducted. Available data from high-resource locations, however, do show benefit of starting ART early during the course of TB therapy to prevent TB incidence (79).
HIV has a profound effect on TB, including faster rates of disease progression, higher rates of drug resistance, and increased mortality among patients with MDR TB. Although HIV testing should be performed on all people with suspected or confirmed TB, rapid molecular assays, such as the Xpert MTB/RIF assay, for detection of both TB and drug resistance should be considered in patients with HIV suspected of having TB. Patients with HIV and MDR TB have a lower mortality when taking ART, and the benefits seen with starting ART in patients with MDR TB, especially those with CD4 cell counts below 50 cells/μl, support the management approach as recommended for patients with drug-susceptible TB. The composition of an effective, nonantagonistic combination ART and anti-TB medication program, along with managing medication intolerances and monitoring patient responses, will require a closely integrated, multidisciplinary health care team.
| 1 . | Shah S; Centers for Disease Control and Prevention (CDC). Mortality among patients with tuberculosis and associations with HIV status—United States, 1993–2008. MMWR Morb Mortal Wkly Rep 2010;59:1509–1513. |
| 2 . | Trieu L, Li J, Hanna DB, Harris TG. Tuberculosis rates among HIV-infected persons in New York City, 2001–2005. Am J Public Health 2010;100:1031–1034. |
| 3 . | Whalen CC, Nsubuga P, Okwera A, Johnson JL, Hom DL, Michael NL, et al. Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda. AIDS 2000;14:1219–1228. |
| 4 . | Badri M, Ehrlich R, Wood R, Pulerwitz T, Maartens G. Association between tuberculosis and HIV disease progression in a high tuberculosis prevalence area. Int J Tuberc Lung Dis 2001;5:225–232. |
| 5 . | Leroy V, Salmi LR, Dupon M, Sentilhes A, Texier-Maugein J, Dequae L, et al. Progression of human immunodeficiency virus infection in patients with tuberculosis disease: a cohort study in Bordeaux, France, 1988–1994. The Groupe d’Epidémiologie Clinique du Sida en Aquitaine (GECSA). Am J Epidemiol 1997;145:293–300. |
| 6 . | López-Gatell H, Cole SR, Margolick JB, Witt MD, Martinson J, Phair JP, et al.; Multicenter AIDS Cohort Study. Effect of tuberculosis on the survival of HIV-infected men in a country with low tuberculosis incidence. AIDS 2008;22:1869–1873. |
| 7 . | Vernon A, Burman W, Benator D, Khan A, Bozeman L. Tuberculosis Trials Consortium. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Lancet 1999;353:1843–1847. |
| 8 . | Lutfey M, Della-Latta P, Kapur V, Palumbo LA, Gurner D, Stotzky G, et al. Independent origin of mono-rifampin–resistant Mycobacterium tuberculosis in patients with AIDS. Am J Respir Crit Care Med 1996;153:837–840. |
| 9 . | Li J, Munsiff SS, Driver CR, Sackoff J. Relapse and acquired rifampin resistance in HIV-infected patients with tuberculosis treated with rifampin- or rifabutin-based regimens in New York City, 1997–2000. Clin Infect Dis 2005;41:83–91. |
| 10 . | Mesfin YM, Hailemariam D, Biadgilign S, Kibret KT. Association between HIV/AIDS and multi-drug resistance tuberculosis: a systematic review and meta-analysis. PLoS One 2014;9:e82235 [Published erratum appears in PLoS One 9:e89709.]. |
| 11 . | Gandhi NR, Weissman D, Moodley P, Ramathal M, Elson I, Kreiswirth BN, et al. Nosocomial transmission of extensively drug-resistant tuberculosis in a rural hospital in South Africa. J Infect Dis 2013;207:9–17. |
| 12 . | Shah NS, Auld SC, Brust JC, Mathema B, Ismail N, Moodley P, et al. Transmission of extensively drug-resistant tuberculosis in South Africa. N Engl J Med 2017;376:243–253. |
| 13 . | Khan PY, Yates TA, Osman M, Warren RM, van der Heijden Y, Padayatchi N, et al. Transmission of drug-resistant tuberculosis in HIV-endemic settings. Lancet Infect Dis 2019;19:e77–e88. |
| 14 . | Centers for Disease Control and Prevention. Online TB Information System (OTIS). [Accessed 2019 Apr 17]. Available from https://wonder.cdc.gov/TB-v2017.html). |
| 15 . | Samuels JP, Sood A, Campbell JR, Ahmad Khan F, Johnston JC. Comorbidities and treatment outcomes in multidrug resistant tuberculosis: a systematic review and meta-analysis. Sci Rep 2018;8:4980. |
| 16 . | Bastard M, Sanchez-Padilla E, du Cros P, Khamraev AK, Parpieva N, Tillyashaykov M, et al. Outcomes of HIV-infected versus HIV–non-infected patients treated for drug-resistance tuberculosis: multicenter cohort study. PLoS One 2018;13:e0193491. |
| 17 . | Gandhi NR, Andrews JR, Brust JC, Montreuil R, Weissman D, Heo M, et al. Risk factors for mortality among MDR- and XDR-TB patients in a high HIV prevalence setting. Int J Tuberc Lung Dis 2012;16:90–97. |
| 18 . | Marks SM, Flood J, Seaworth B, Hirsch-Moverman Y, Armstrong L, Mase S, et al.; TB Epidemiologic Studies Consortium. Treatment practices, outcomes, and costs of multidrug-resistant and extensively drug-resistant tuberculosis, United States, 2005–2007. Emerg Infect Dis 2014;20:812–821. |
| 19 . | World Health Organization. Rapid communication: key changes to treatment of multidrug-and rifampicin-resistant tuberculosis (MDR/RR-TB). Geneva: World Health Organization; 2018. |
| 20 . | World Health Organization. WHO treatment guidelines for drug-resistant tuberculosis 2016 update. Geneva:World Health Organization; 2016. |
| 21 . | U.S. Department of Health and Human Services Services. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. 2017 [updated 2017 Sep 22; 2019 Feb 4]. Available from: https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-opportunistic-infection/325/tb. |
| 22 . | Curry International Tuberculosis Center and California Department of Public Health. Drug-resistant tuberculosis: a survival guide for clinicians, 3rd edition. 2016 [accessed 2019 Jun 18]. Available from: http://www.currytbcenter.ucsf.edu/products/cover-pages/drug-resistant-tuberculosis-survival-guide-clinicians-3rd-edition. |
| 23 . | Ahmad N, Ahuja SD, Akkerman OW, Alffenaar JC, Anderson LF, Baghaei P, et al.; Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet 2018;392:821–834. |
| 24 . | Taylor Z, Nolan CM, Blumberg HM. Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recomm Rep 2005;54:1–81. |
| 25 . | Branson BM, Handsfield HH, Lampe MA, Janssen RS, Taylor AW, Lyss SB, et al.; Centers for Disease Control and Prevention (CDC). Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep 2006;55:1–17, quiz CE1–CE4. |
| 26 . | Migliori GB, Zellweger J-P, Abubakar I, Ibraim E, Caminero JA, De Vries G, et al. European union standards for tuberculosis care. Lausanne, Switzerland: European Respiratory Society; 2012. |
| 27 . | World Health Organization. WHO policy on collaborative TB/HIV activities: guidelines for national programmes and other stakeholders 2012. Geneva: World Health Organization; 2014. |
| 28 . | World Health Organization. Implementing the end TB strategy: the essentials. Geneva: World Health Organization; 2015. |
| 29 . | Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis 2017;64:111–115. |
| 30 . | Centers for Disease Control and Prevention (CDC). Updated guidelines for the use of nucleic acid amplification tests in the diagnosis of tuberculosis. MMWR Morb Mortal Wkly Rep 2009;58:7–10. |
| 31 . | World Health Organization. The use of lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis and screening of active tuberculosis in people living with HIV: policy guidance. Geneva: World Health Organization; 2015. No. 9241509635. |
| 32 . | Lawn SD. Point-of-care detection of lipoarabinomannan (LAM) in urine for diagnosis of HIV-associated tuberculosis: a state of the art review. BMC Infect Dis 2012;12:103. |
| 33 . | Cox HS, Mbhele S, Mohess N, Whitelaw A, Muller O, Zemanay W, et al. Impact of Xpert MTB/RIF for TB diagnosis in a primary care clinic with high TB and HIV prevalence in South Africa: a pragmatic randomised trial. PLoS Med 2014;11:e1001760. |
| 34 . | Raizada N, Sachdeva KS, Sreenivas A, Kulsange S, Gupta RS, Thakur R, et al. Catching the missing million: experiences in enhancing TB & DR-TB detection by providing upfront Xpert MTB/RIF testing for people living with HIV in India. PLoS One 2015;10:e0116721. |
| 35 . | Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 2010;363:1005–1015. |
| 36 . | Dorman SE, Schumacher SG, Alland D, Nabeta P, Armstrong DT, King B, et al.; study team. Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre diagnostic accuracy study. Lancet Infect Dis 2018;18:76–84. |
| 37 . | Opota O, Zakham F, Mazza-Stalder J, Nicod L, Greub G, Jaton K. Added value of Xpert MTB/RIF Ultra for diagnosis of pulmonary tuberculosis in a low-prevalence setting. J Clin Microbiol 2019;57:e01717–e01718. |
| 38 . | Barnard M, Gey van Pittius NC, van Helden PD, Bosman M, Coetzee G, Warren RM. The diagnostic performance of the GenoType MTBDRplus version 2 line probe assay is equivalent to that of the Xpert MTB/RIF assay. J Clin Microbiol 2012;50:3712–3716. |
| 39 . | Centers for Disease Control and Prevention. Reference Laboratory Division of TB Elimination Laboratory User Guide for U.S. Public Health Laboratories: Molecular Detection of Drug Resistance (MDDR) in Mycobacterium tuberculosis Complex by DNA sequencing (version 2.0). 2015 [accessed 2019 Jun 18]. Available from: https://www.cdc.gov/tb/topic/laboratory/mddrusersguide.pdf. |
| 40 . | Lowenthal P, Lin S-YG, Desmond E, Shah N, Flood J, Barry PM. Evaluation of the impact of a sequencing assay for detection of drug resistance on the clinical management of tuberculosis. Clin Infect Dis 2019;69:668–675. |
| 41 . | Lin S-YG, Rodwell TC, Victor TC, Rider EC, Pham L, Catanzaro A, et al. Pyrosequencing for rapid detection of extensively drug-resistant Mycobacterium tuberculosis in clinical isolates and clinical specimens. J Clin Microbiol 2014;52:475–482. |
| 42 . | Shea J, Halse TA, Lapierre P, Shudt M, Kohlerschmidt D, Van Roey P, et al. Comprehensive whole-genome sequencing and reporting of drug resistance profiles on clinical cases of Mycobacterium tuberculosis in New York State. J Clin Microbiol 2017;55:1871–1882. |
| 43 . | Arentz M, Pavlinac P, Kimerling ME, Horne DJ, Falzon D, Schünemann HJ, et al.; ART study group. Use of anti-retroviral therapy in tuberculosis patients on second-line anti-TB regimens: a systematic review. PLoS One 2012;7:e47370. |
| 44 . | Pietersen E, Ignatius E, Streicher EM, Mastrapa B, Padanilam X, Pooran A, et al. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet 2014;383:1230–1239. |
| 45 . | Dheda K, Shean K, Zumla A, Badri M, Streicher EM, Page-Shipp L, et al. Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study. Lancet 2010;375:1798–1807. |
| 46 . | Kvasnovsky CL, Cegielski JP, Erasmus R, Siwisa NO, Thomas K, der Walt ML. Extensively drug-resistant TB in Eastern Cape, South Africa: high mortality in HIV-negative and HIV-positive patients. J Acquir Immune Defic Syndr 2011;57:146–152. |
| 47 . | Satti H, McLaughlin MM, Hedt-Gauthier B, Atwood SS, Omotayo DB, Ntlamelle L, et al. Outcomes of multidrug-resistant tuberculosis treatment with early initiation of antiretroviral therapy for HIV co-infected patients in Lesotho. PLoS One 2012;7:e46943. |
| 48 . | Blanc F-X, Sok T, Laureillard D, Borand L, Rekacewicz C, Nerrienet E, et al.; CAMELIA (ANRS 1295–CIPRA KH001) Study Team. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011;365:1471–1481. |
| 49 . | Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010;362:697–706. |
| 50 . | Havlir DV, Kendall MA, Ive P, Kumwenda J, Swindells S, Qasba SS, et al.; AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011;365:1482–1491. |
| 51 . | Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray AL, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011;365:1492–1501. |
| 52 . | Padayatchi N, Abdool Karim SS, Naidoo K, Grobler A, Friedland G. Improved survival in multidrug-resistant tuberculosis patients receiving integrated tuberculosis and antiretroviral treatment in the SAPiT Trial. Int J Tuberc Lung Dis 2014;18:147–154. |
| 53 . | World Health Organization. Treatment of tuberculosis: guidelines. Geneva: World Health Organization; 2010. |
| 54 . | Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Official American Thoracic Society/centers for disease control and prevention/infectious diseases society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis;63:e147–e195. |
| 55 . | Brust JC, Lygizos M, Chaiyachati K, Scott M, van der Merwe TL, Moll AP, et al. Culture conversion among HIV co-infected multidrug-resistant tuberculosis patients in Tugela Ferry, South Africa. PLoS One 2011;6:e15841. |
| 56 . | Tierney DB, Franke MF, Becerra MC, Alcántara Virú FA, Bonilla CA, Sánchez E, et al. Time to culture conversion and regimen composition in multidrug-resistant tuberculosis treatment. PLoS One 2014;9:e108035. |
| 57 . | Shibabaw A, Gelaw B, Wang S-H, Tessema B. Time to sputum smear and culture conversions in multidrug resistant tuberculosis at University of Gondar Hospital, Northwest Ethiopia. PLoS One 2018;13:e0198080. |
| 58 . | Kurbatova EV, Cegielski JP, Lienhardt C, Akksilp R, Bayona J, Becerra MC, et al. Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies. Lancet Respir Med 2015;3:201–209. |
| 59 . | Meintjes G, Wilkinson RJ, Morroni C, Pepper DJ, Rebe K, Rangaka MX, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010;24:2381–2390. |
| 60 . | Meintjes G, Stek C, Blumenthal L, Thienemann F, Schutz C, Buyze J, et al.; PredART Trial Team. Prednisone for the prevention of paradoxical tuberculosis-associated IRIS. N Engl J Med 2018;379:1915–1925. |
| 61 . | Vinnard C, King L, Munsiff S, Crossa A, Iwata K, Pasipanodya J, et al. The long-term mortality of patients with tuberculosis meningitis in New York City: a cohort study. Clin Infect Dis 2017;64:401–407. |
| 62 . | Thwaites GE, Lan NTN, Dung NH, Quy HT, Oanh DT, Thoa NT, et al. Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis. J Infect Dis 2005;192:79–88. |
| 63 . | Török ME, Yen NTB, Chau TTH, Mai NTH, Phu NH, Mai PP, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)—associated tuberculous meningitis. Clin Infect Dis 2011;52:1374–1383. |
| 64 . | Garg RK, Jain A, Malhotra HS, Agrawal A, Garg R. Drug-resistant tuberculous meningitis. Expert Rev Anti Infect Ther 2013;11:605–621. |
| 65 . | Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs 2014;74:839–854 [Published erratum appears in Drugs 74:2061.] |
| 66 . | U.S. Centers for Disease Control and Prevention. Managing drug interactions in the treatment of HIV-related tuberculosis. 2013 [2019 Apr 1]. Available from: https://www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/default.htm. |
| 67 . | Rossouw TM, Feucht UD, Melikian G, van Dyk G, Thomas W, du Plessis NM, et al. Factors associated with the development of drug resistance mutations in HIV-1 infected children failing protease inhibitor-based antiretroviral therapy in South Africa. PLoS One 2015;10:e0133452. |
| 68 . | Ehret GB, Voide C, Gex-Fabry M, Chabert J, Shah D, Broers B, et al. Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. Arch Intern Med 2006;166:1280–1287. |
| 69 . | Han S, Zhang Y, Chen Q, Duan Y, Zheng T, Hu X, et al. Fluconazole inhibits hERG K(+) channel by direct block and disruption of protein trafficking. Eur J Pharmacol 2011;650:138–144. |
| 70 . | Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866–1874. |
| 71 . | Goswami ND, Mase S, Griffith D, Bhavaraju R, Lardizabal A, Lauzardo M, et al. Tuberculosis in the United States: medical consultation services provided by 5 tuberculosis regional training and medical consultation centers, 2013-2017. Open Forum Infect Dis 2019;6:ofz167. |
| 72 . | Blasi F, Dara M, van der Werf MJ, Migliori GB. Supporting TB clinicians managing difficult cases: the ERS/WHO Consilium. Eur Respir J 2013;41:491–494. |
| 73 . | Van Deun A, Maug AKJ, Salim MAH, Das PK, Sarker MR, Daru P, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010;182:684–692. |
| 74 . | Aung KJ, Van Deun A, Declercq E, Sarker MR, Das PK, Hossain MA, et al. Successful ‘9-month Bangladesh regimen’ for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis 2014;18:1180–1187. |
| 75 . | Kuaban C, Noeske J, Rieder HL, Aït-Khaled N, Abena Foe JL, Trébucq A. High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon. Int J Tuberc Lung Dis 2015;19:517–524. |
| 76 . | Piubello A, Harouna SH, Souleymane MB, Boukary I, Morou S, Daouda M, et al. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis 2014;18:1188–1194. |
| 77 . | Trébucq A, Schwoebel V, Kashongwe Z, Bakayoko A, Kuaban C, Noeske J, et al. Treatment outcome with a short multidrug-resistant tuberculosis regimen in nine African countries. Int J Tuberc Lung Dis 2018;22:17–25. |
| 78 . | Nunn AJ, Phillips PPJ, Meredith SK, Chiang C-Y, Conradie F, Dalai D, et al.; STREAM Study Collaborators. A trial of a shorter regimen for rifampin-resistant tuberculosis. N Engl J Med 2019;380:1201–1213. |
| 79 . | Pettit AC, Mendes A, Jenkins C, Napravnik S, Freeman A, Shepherd BE, et al. Timing of antiretroviral treatment, immunovirologic status and TB risk: Implications for test and treat. J Acquir Immune Defic Syndr 2016;72:572–578. |
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Author Contributions: J.W.W. served as principle author. J.W.W., D.N.M., and S.M.M. contributed to the composition, content, structure, and writing of the manuscript.
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