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Associate Physician, Clinical Instructor Vol.
Division of HIV, ID & Global Medicine
University of California, San Francisco
HIV & Addiction Medicine Physician
San Francisco Department of Public Health
Street Medicine & Shelter Health
Ward 86 Positive Health Program
San Francisco, California
Nicky Mehtani, MD, MPH, has no relevant conflicts of interest to report.
Last summer, a long-term occupant of a homeless shelter in San Francisco was diagnosed with active pulmonary tuberculosis. As part of the city’s public health response, all other occupants of the shelter were tested for latent tuberculosis infection (LTBI). Of these, 4 were my primary care patients. As the Clinical Director of HIV Homeless Outreach & Mobile Engagement (HHOME)—a street-based intensive case management and primary care program designed to serve people experiencing homelessness with HIV/AIDS, psychiatric co-morbidities, and substance use disorders who have been unable to tolerate 4-wall clinic settings—I am accustomed to working creatively with a multi-disciplinary team to minimize barriers to our patients’ medical treatment plans. Even so, addressing a TB outbreak resulting in a high prevalence of LTBI in a socially and medically complex patient population raised challenges.
What special considerations are there in diagnosing LTBI in people with HIV (PWH)?
In the general population, the lifetime risk of developing active tuberculosis is 5% to 10% following initial infection; however, among PWH not taking antiretroviral treatment (ART), the annual risk is 10% and increases with declining CD4+ cell counts. Thus, prompt diagnosis and treatment of LTBI in PWH is critical.
Diagnosing LTBI can be done using a tuberculin skin test (TST) or interferon gamma release assay (IGRA)—both of which indirectly assess immunologic response to mycobacterial antigens. In our setting, IGRAs—which require only 1 patient visit for a lab draw—are more practical given the difficulty of tracking down patients for PPD readings 48 to 72 hours after placement of TST. However, 2 of my 4 affected patients had CD4+ cell counts < 200 cells/mm3 at the time of TB exposure, which confers an increased risk of a false negative IGRA result. Such individuals should have a repeat assessment once their CD4+ cell levels are > 200 cells/mm3 to increase diagnostic sensitivity. An additional consideration is that IGRAs and TST may take several weeks to turn positive after TB exposure and infection. Accordingly, when an initial IGRA is negative within 8 weeks of an exposure, a repeat test should be performed at least 8 to 10 weeks after exposure and “window prophylaxis” (i.e. treatment for presumed LTBI) considered for immunocompromised people during that period given a higher risk of developing severe TB.
How do LTBI treatment recommendations differ among PWH and those without HIV?
There are now numerous treatment options for LTBI in the general population, including various combinations of isoniazid (INH), rifampin (RIF), and rifapentine (RPT), which range in length from 9 months of treatment to as little as 1 month. However, the guideline-recommended options for LTBI treatment among PWH are more limited due to numerous drug-drug-interactions between ART regimens and rifamycins, as well as limited data regarding the use of newer LTBI regimens among PWH. In some cases, the various guidelines—including those developed by the CDC, WHO, and DHHS—are even at odds with one another.
Historically, the most robust data on the benefits of TB preventative therapy have been for the use of INH among PWH, and INH has no significant drug interactions with modern ART medications. However, the efficacy of 9 months of isoniazid (9H) is diminished by high non-completion rates—ranging from 47% to 53% in U.S. TB programs. Thus, in a patient population such as ours, for which there exist several logistical barriers to daily long-term medication adherence, 9H may not always be the most effective option.
Shorter-course rifamycin-based regimens, such as 3 months of once-weekly INH and RPT (3HP), 4 months of daily RIF (4R), 3 months of daily INH and RIF (3HR), or even 1 month of daily INH and RPT (1HP) may be more effective in some settings. Each of these regimens is considered as a “preferred” or “alternative” recommended regimen for LTBI treatment in PWH by at least 1 set of global or national U.S. guidelines (CDC, WHO, or DHHS). Notably, the U.S. National TB Controllers Association and CDC guidelines now recommend shorter-course rifamycin therapies preferentially over INH for most individuals. However, if considering one of these regimens, detailed attention must be given to a multitude of drug-drug-interactions between rifamycins and ART medications.
How did our LTBI treatment plans differ based on patient-specific factors?
Within a few weeks of extended exposure to TB in the homeless shelter, all 4 of our patients agreed to contact testing with an IGRA assay. One patient had a negative result and the other 3 had positive test results. All were asymptomatic and had unremarkable chest x-ray findings. Treatment courses for each patient differed dependent on a variety of patient-specific factors, as noted below.
CD4+ cell count: 175 cells/mm3
HIV-1 RNA: 2,400 copies/mL
This patient’s initial IGRA test was negative. But because her IGRA was obtained 2 to 4 weeks after her most recent exposure to active TB and she was known to be immunocompromised, “window prophylaxis” with daily INH was administered until a repeat IGRA was obtained 8 to 10 weeks post-exposure. By this point, her CD4+ cell count had also increased to > 200 cells/mm3, and we felt more confident in interpretation of negative LTBI test results.
CD4+ cell count: 590 cells/mm3
HIV-1 RNA: undetectable
Our second patient had excellent adherence to ART and had been checking in with a medical case manager at least once weekly. It was felt that 3HP—which would require a total of only 12 total doses of LTBI treatment—would be ideal, as it could be administered as directly-observed therapy by his medical case manager during outreach visits. However, 3HP is contraindicated with both bictegravir (BIC) and tenofovir alafenamide (TAF). After discussing the pros and cons, the patient ultimately decided to switch to DTG + TDF/FTC for the duration of LTBI treatment to accommodate the 3HP regimen. Though DTG is not currently recommended in combination with RPT in official guidelines (due to decreased DTG concentrations and a theoretical risk of treatment failure or developing resistance), recent studies have demonstrated favorable results for patients who maintain excellent adherence to DTG while receiving 3HP: though DTG concentrations were reduced, they remained above the IC90 in almost all individuals. (Of note, this has not been the case when BIC is combined with RPT). TAF is also not recommended in combination with rifamycins for most individuals due to decreased blood and intracellular tenofovir concentrations, though recent data suggests that intracellular tenofovir levels are higher with TAF and rifampin coadministration than with TDF alone.10,18 Nonetheless, given minimal risks of TDF-associated bone or renal toxicities in this patient, TAF was temporarily exchanged for TDF during LTBI treatment to allow for 3HP use.
CD4+ cell count: 90 cells/mm3
HIV-1 RNA: 525,000 copies/mL
ART: DTG + DRV/c/TAF/FTC
In contrast to Patient #2, our third patient had relatively poorly controlled HIV and had been maintained on a more complex ART regimen, which was necessary due to a history of inconsistent adherence and multiple NNRTI mutations. There was significant concern about the possibility of treatment non-completion with 9H or 6H, particularly given his low CD4+ cell count and high risk of progression to active TB. Though theoretically it may have been possible to alter the patient’s ART regimen to allow for a shorter-course LTBI treatment, given the risk of further resistance development due to decreased ART concentrations if using a rifamycin, it was ultimately felt that daily isoniazid (9H), combined with aggressive adherence support for daily ART, would be the safest treatment option.
CD4+ cell count: 425 cells/mm3
HIV-1 RNA: undetectable
Our last patient was a unique case in that she was an HIV elite controller, meaning she has been able to maintain an undetectable HIV viral load even when not taking ART. She had initiated EFV/TDF/FTC in the distant past and was very resistant to the idea of changing her regimen or taking any additional medications for extended periods of time. However, she was willing to complete a shorter course LTBI treatment regimen. Given these parameters, 3HP was considered as a potential option, and it is supported by all sets of global and national LTBI treatment guidelines when combined with EFV/TDF/FTC. Though not explicitly mentioned in the CDC or DHHS guidelines, there are also data to suggest that one month of daily INH and RPT (1HP) is an effective regimen to treat LTBI among people taking EFV/TDF/FTC. The WHO guidelines thus list 1HP as an “alternative” option for such patients. Our patient was ultimately treated with 3HP given that 1HP has not yet been extensively studied in low-TB prevalence areas.
HIV-ASSIST: Resource to help guide complex clinical decisions for providers caring for PWH
Given the current heterogeneity in the various published global and national U.S. guidelines, when considering LTBI treatment options for PWH, it is helpful to reflect upon the primary data backing specific combinations of ART and LTBI treatments. However, primary literature review can be an arduous and time-consuming process and is not always feasible in the context of a busy clinical practice. In such settings, I’ve found HIVASSIST.com to be a useful aid when designing patient-centered ART regimens. HIV-ASSIST is a free, online educational tool that integrates a variety of patient-specific data points—including HIV resistance mutations, adherence patterns, comorbidities, comedications, prior and current ART regimens, HLA-B*5701 status, pregnancy status, tropism, and HIV viral load—to empower clinical decision-making. The online tool weighs the clinical evidence about pros and cons of medication combinations, cites the primary literature used to create our global and national guidelines and delivers this information in easy-to-digest educational summaries, providing specific rationale for each evidence-based ART option. HIV-ASSIST has the advantage of being updated frequently in response to guideline changes or new data—such as the emerging treatment and pharmacokinetic studies used to make the nuanced LTBI treatment decisions above. Importantly, the site’s algorithms weigh the uncertainty across various domains (e.g., adherence, pill burden, drug interactions, evidence for effectiveness), incorporating this complexity into ranking potential ART options. Rather than suggesting a single “right” approach to ART selection, HIV-ASSIST’s goal is to support clinicians with the relevant information they need to make their own data-driven decisions in one, convenient place.
How would you have approached managing these PWH following an exposure to TB? Answer the polling question and join the conversation by posting in the discussion section.