Thank you for your interest in CCO content. As a guest, please complete the following information fields. These data help ensure our continued delivery of impactful education.
Become a member (or login)? Member benefits include accreditation certificates, downloadable slides, and decision support tools.
Adjunct Instructor of Medicine
Johns Hopkins School of Medicine
Paul Pham, PharmD, BCPS, has disclosed that he has ownership interest in AbbVie and Gilead Sciences.
Antiretroviral therapy (ART) changes are sometimes necessary despite having achieved HIV viral suppression. For example, we might want to mitigate antiretroviral (ARV) interactions with comedications or comorbidities. In these situations, HIV-ASSIST can help healthcare providers integrate multiple clinical considerations and identify alternative ARV regimens, informed by current treatment principles outlined in clinical practice guidelines. The following case of a patient with HIV and pulmonary tuberculosis (TB) illustrates how HIV-ASSIST was used to guide switching ARV regimens.
HIV and Pulmonary TB
We recently cared for a 57-year-old man with HIV diagnosed more than 10 years ago, whose previous regimens included protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs). Virus genotyping showed the M184V and K70E mutations, both conferring resistance to NRTIs. Following the Department of Health and Human Services (DHHS) guidance on management of virologic failure, his HCPs at the time started a regimen with ≥2 active agents: elvitegravir (EVG)/cobicistat (COBI)/tenofovir alafenamide (TAF)/emtricitabine (FTC) + darunavir (DRV).
During the following year, the patient experienced low-level viremia on this regimen, and a subsequent genotype revealed the T66A, E138K, and S147G mutations (conferring integrase strand transfer inhibitor [INSTI] resistance) along with the previously identified M184V and K70E. At this point, PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs) remained as drug classes that were likely to be fully active; consequently, the HCPs chose to switch to DRV/COBI/ TAF/FTC + doravirine (DOR) and the patient was subsequently virally suppressed for several years with CD4+ cell counts >450 cells/mm3.
Recently, the patient presented with a 3-month history of weight loss (30 lb) and a productive cough. His CD4+ cell count was 325 cells/mm3 and his HIV-1 RNA remained undetectable, but chest CT showed bilateral cavitary pneumonia. Mycobacterial evaluation yielded sputum samples that were AFB smear positive (4+), nucleic acid amplification test positive with no rpoB mutation (by GeneXpert MTB/RIF), and eventually culture positive for Mycobacterium tuberculosis that was pan-sensitive to all first-line TB drugs.
The treating team wanted to start first-line TB therapy with isoniazid, pyrazinamide, ethambutol, and a rifamycin, and they had to consider several ART/TB drug–drug interactions. Rifampin is contraindicated for coadministration with PIs, so the team initiated rifabutin (RBT) as the rifamycin component in the patient’s TB therapy. The use of RBT led the team to make several other adjustments, as well. First, TAF was switched to tenofovir disoproxil fumarate (TDF), based on DHHS recommendations on the interaction between rifabutin and TAF. Second, the DOR dose was increased from daily to twice daily in the setting of rifabutin coadministration. Third, the team considered the possibility that his DRV/COBI would increase RBT levels, as has been reported with DRV/ritonavir (RTV)—so the RBT dose was reduced from a standard 300 mg/day orally to 150 mg/day orally.
Several months later, the patient transitioned to care in our health department, where an HIV/TB team reviewed his clinical course and treatment. The team noted that the microbiologic response to TB therapy had been slower than typically observed. Specifically, it took nearly 90 days for his mycobacterial sputum cultures to become negative. Although the time to convert to culture-negative status varies among patients (based on degree of initial lung cavitation and bacillary load), we typically anticipate culture conversion within the first 60 days for most patients, including those with HIV coinfection.
Our team considered potential causes of the observed delay in culture conversion, including inadequate TB drug levels, nonadherence (felt to be unlikely since we had implemented directly observed therapy), and acquired TB drug resistance. We obtained therapeutic drug levels: His 2-hour and 6-hour postdose RBT concentrations were 0.14 µg/mL and 0.12 µg/mL, respectively (normal: 0.3-0.9 µg/mL). (The RBT active metabolite levels were also low.) A repeat HIV-1 RNA was obtained (undetectable), and repeat sputum testing showed no TB drug resistance. We concluded that his subtherapeutic drug levels were implicated in his slow microbiologic response, and we were concerned that this could affect the ultimate outcome of his TB treatment. Although the patient was still virally suppressed, we consulted HIV-ASSIST to reassess his HIV and TB therapy.
After entering the patient and viral attributes on the input screen, the tool provided a ranked list of potential ARV regimens. HIV-ASSIST assesses the degree of activity of all available ARVs based on the penalty scores assigned by the Stanford HIV Drug Resistance Database; drugs with partial or high degree of resistance are excluded or weighted to be less preferred in the algorithm’s recommendations. These drug resistance “penalties” are displayed in a consolidated form from the HIV-ASSIST Results screen (under the Additional Information tab). All regimens were assigned scores >3, reflecting the presence of uncertainty in the evidence (ie, limited clinical trial data) for virologic effectiveness of suggested ARV combinations (particularly in treatment-experienced patients), or unfavorable characteristics of the regimens (eg, twice-daily dosing, pill burden). In such settings, the HIV-ASSIST tool provides additional embedded information to guide ultimate regimen selection.
History of Drug Resistance
The drug resistance evaluation in this instance reflected the fact that PIs and NNRTIs are expected to be fully active drugs, with some NRTIs or some INSTIs available as partially active drugs (eg, low level resistance to dolutegravir and bictegravir). Current guidelines and evidence suggest that within-class ARV switches usually maintain viral suppression, provided there is no drug resistance to the newly substituted ARV; consequently, HIV-ASSIST prioritizes regimens with similar drug classes and number of active drugs to the regimen that has led to virologic suppression. Between-class switches are also considered in the HIV-ASSIST algorithms, provided that there is no resistance to new components. Among the reasons to consider switching regimens in virally suppressed patients is the desire to reduce pill burden, so HIV-ASSIST assesses the number of pills of any new proposed regimen vs those in the current suppressive regimen. Factoring in these considerations, regimens consisting of 2 NRTIs with a boosted PI and an NNRTI rose to the top of the HIV-ASSIST recommendations.
Each 1-to-1 drug interaction in the HIV-ASSIST database is evaluated based on FDA labeling, available data in the University of Liverpool HIV Drug interactions checker, and drug interaction tables in the DHHS guidelines. Drug combinations that are contraindicated are given a “penalty score” that excludes them from the final HIV-ASSIST recommendations. Less significant drug interactions are “weighted” to reflect the degree to which the interaction is likely to affect regimen effectiveness or tolerability.
As previously mentioned, rifampin is contraindicated with all COBI- or RTV-boosted PI regimens due to potent CYP3A4 induction. RBT, however, may be considered with RTV-boosted PIs owing to less potent CYP450 induction that has been shown to cause only a moderate decrease in PI concentrations. However, it is important to recognize 2 additional considerations that were highlighted, among many others, under the HIV-ASSIST Additional Information tab (Comedication Warnings).
First, RTV-boosted PIs are anticipated to increase RBT metabolite levels by up to 880%, and consequently, current recommendations suggest a dose reduction of RBT to 150 mg once daily. Secondly, COBI and RTV are not necessarily interchangeable in terms of their drug interaction profile, something not always recognized by providers. For example, when RTV-boosted EVG is coadministered with RBT, EVG concentrations are not significantly affected. But when COBI-boosted EVG is coadministered with RBT, COBI concentrations are reduced by 72%, leading to insufficient boosting of EVG. This has been shown to cause a 21% decrease in EVG area under the curve, and a 67% decrease in EVG trough concentration.
Although RBT with DRV/COBI has not been explicitly studied, a similar impact on the pharmacokinetic enhancer may be expected. In vitro studies have suggested that COBI was less potent than RTV at overcoming rifamycin-related CYP3A4 induction and increased DRV clearance. Therefore, there is the risk of subtherapeutic DRV levels when DRV/COBI and RBT are coadministered. It is also possible that with reduced COBI concentrations, the boosting effect of COBI on RBT is concomitantly reduced. We postulated that this complex multiway interaction contributed to the observed subtherapeutic RBT drug concentrations in our patient.
After reviewing the HIV-ASSIST recommendations and educational resources, our team decided to modify the patient’s ART regimen by switching his DRV/COBI to DRV/RTV. We also considered replacing DOR with an alternative NNRTI (such as efavirenz or rilpivirine, which emerged as other alternative regimens at the top of the HIV-ASSIST recommendation list), which would yield a once-daily regimen. Ultimately, however, the patient and team shared a preference to make as few changes as possible to the suppressive ART regimen that the patient had been tolerating, so we opted to keep DOR despite the need for twice-daily dosing during TB therapy. The patient was maintained on DRV/RTV + TDF/FTC and DOR twice daily while receiving TB therapy, with close monitoring and maintenance of virologic suppression.
ARV selection in patients with HIV and TB coinfection can be complex, particularly in individuals who have underlying ARV drug resistance. The current DHHS guidelines recommend consultation with an HIV specialist when planning a regimen switch in patients with virologic suppression with a history of drug resistance, as was the situation for our patient. In this complex case, we believe even experienced clinicians can benefit from the additional availability of decision support tools such as HIV-ASSIST (www.hivassist.com).
How would you manage ARV regimen switch in a patient with HIV/TB coinfection? Answer the polling question and join the conversation by posting in the discussion section.