Rajeev Shah, PharmD, AAHIVP, BCIDP

 (TB) is a serious health concern, especially when coupled with HIV. Individuals with 

 are more likely to become sick if they are coinfected with TB. Infections among individuals with TB include those in the following categories:

Active (disease mainly affects the lungs and is spread individual to individual through airborne transmission) 

Extensively drug resistant (TB that is resistant to isoniazid and rifampin, plus any fluoroquinolone and a second-line injectable drug)

 but without symptoms and cannot spread it to others and may never develop active TB)

Multidrug resistant (there is drug resis- tance to the 2 most potent TB medications, isoniazid and rifampin)

It is estimated that up to 13 million individuals in the United States have latent TB, but the incidence in individuals with HIV is not known. In 2020, of 6960 individuals in the United States who had diagnoses of active TB, 300—or 4.3%—had HIV.

 Consequences of untreated TB, along with HIV, can lead to significant morbidity and mortality. Consequently, medication initi- ation for the management of HIV and TB tends to be complex, because concomitant drug interactions often affect treatment.

Rifamycin derivatives, such as rifabutin and rifampin, are core components of first-line TB treatment regimens. Unfortunately, they have the potential to cause drug-drug interactions through either enzymatic and/or transporter induction, not only with established first-line agents for the treatment of HIV but also those newly approved. This review will summarize rifamycin drug-drug interactions with novel agents and combinations, such as fostemsavir, tenofovir alafenamide (TAF), and 2-drug regimens (2DR).

Historically, TAF has been contraindicated with rifamycin, and tenofovir disoproxil fumarate (TDF) has been the preferred formulation. However, newer pharmacokinetic data suggest that concurrent therapy with TAF may be acceptable. This is particularly important, because TAF is often a key component of many first-line regimens for patients who have just received diagnoses of TB.

The results of one study show that coadministration of rifampin and TAF led to a decrease in plasma tenofovir area under the curve (AUC) and concentration at 24 hours by 54% and 55%, respectively.

 However, intracellular tenofovir diphosphate (TFV- DP) AUC remained 4-fold higher than those of TDF administered alone. Because the TFV-DP AUC at the site of action was higher, this shows promise for maintaining efficacy when rifampin and TAF are coadministered. Data regarding clinical outcomes are lacking, so coadministration of rifampin and TAF should only be considered when benefits outweigh risks.

Fostemsavir is a novel agent for the treatment of multidrug-resistant HIV. Rifampin significantly reduces concentrations and exposure of the active metabolite temsavir, so coadministration is contraindicated.

 Rifabutin may be considered an alternative, because it only lowers temsavir AUC and minimum concentration by 30% and 41%, respectively.

 However, there are limited clinical data on efficacy with coadministration, and in the setting of multidrug- resistant HIV, these decreases may contribute to virologic failure of a fostemsavir-containing regimen.

Although there are pharmacokinetic data examining the effect of rifamycin on individual components of 2DR, there is a paucity of clinical data on the management of TB with 2DR. Dolutegravir, a cornerstone agent in oral 2DRs, continues to be evaluated for its role in HIV and TB coinfection.

 Dolutegravir/rilpivirine may be considered in the presence of rifabutin, but a supplemental dose of rilpivirine 25 mg daily with a meal must be given, because of decreased concentrations of rilpivirine in the presence of rifabutin. No significant changes in concentrations were observed when rifabutin was coadministered with dolutegravir.

Similarly, dolutegravir/lamivudine may be considered in the presence of rifabutin and does not require supplemental dosing for either agent.

 Neither rifampin nor rifapentine should be coadministered with dolutegravir/rilpivirine, because of the extensive enzymatic induction of rilpivirine metabolism. As for dolutegravir/lamivudine, a supplemental dose of dolutegravir 50 mg separated 12 hours from dolutegravir/lamivudine may be considered, although formal studies have not been conducted.

 The additional dose of dolutegravir 50 mg should be continued 2 weeks after stopping rifampin or rifapentine, because inducing properties may continue even after discontinuing a strong inducer.

The newest 2DR is long-acting injectable cabotegravir/rilpivirine. No drug-drug interaction studies have been completed between the rifamycins and the long- acting injectable cabotegravir/rilpivirine formulation, and it is unclear whether any dosage adjustments could overcome the potential interaction.

 If a patient requires a rifamycin while on injectable therapy, transition to an alternative regimen should be considered.

Managing drug-drug interactions in HIV/TB coinfection can be complex. As new studies are published and recommendations may change, best practices call for referring to resources such as the US Department of Health & Human Services HIV guidelines or the University of Liverpool HIV drug interaction checker.

, is a clinical associate professor at the University of Illinois Chicago College of Pharmacy.

, is a clinical pharmacy specialist, infectious diseases, at Lifespan in Providence, Rhode Island, and an assistant professor of medicine at the Warren Alpert Medical School of Brown University in Providence.

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Articles

Best practices call for referring to resources, such as those from HHS and the University of Liverpool.

Managing Drug Interactions in HIV and TB Coinfection Is Complex

Patients living with HIV (PLWH) must take daily medications to suppress the virus, despite significant advancements in antiretroviral therapy (ART).

A major limitation of ART is that it is only effective against an actively replicating virus. Therefore, despite being successful in suppressing HIV RNA, ART cannot inhibit a nonreplicating virus. The latter is a contributing reason why HIV cannot be cured with ART alone. Contemporary efforts for therapy have focused on using the immune system to target HIV.

One strategy being investigated to replace daily ART is to use broadly neutralizing antibodies (bNAbs). These antibodies form naturally during an acute HIV infection but are typically not potent enough to completely eradicate the virus. However, a small subset of PLWH, known as 

, maintain their CD4 count even without ART. In these patients, bNAbs are part of the immune response that suppresses the virus. The antibodies in development are derived from long-term nonprogressors and target the genetically conserved regions of the HIV envelope, such as the CD4 binding site, gp120, gp120-gp-41 interface, membrane proximal external region, V1V2 apex, or V3 loop. They have numerous proposed mechanisms, including direct elimination of HIV RNA, enhanced HIV-specific CD8+ T-cell activity, and possible reduction of the HIV reservoir.

Like ART, bNAb monotherapy is associated with the development of resistance, so several bNAbs are being studied in combination. Two antibodies that have shown in vivo activity in PLWH are 3BNC117, which targets the CD4 binding site, and 10-1074, which targets the V3 loop. These agents display long half-lives of 9 and 13 days for 3BNC117 and 10-1074, respectively, which make them attractive options to replace daily ART.

Three doses of 30 mg/kg of 3BNC117 and 10-1074 were given every 3 weeks to individuals with undetectable viral loads who stopped ART. Combination bNAb therapy maintained viral suppression for a median of 21 weeks in subjects with bNAb-susceptible HIV.

 In 4 individuals with bNAb-susceptible virus, 3BNC117 and 10-1074 showed a maximal decrease in mean HIV viral load by 112 copies/mL.

 After completion of therapy, 3 subjects developed elevated inhibitory concentrations to 10-1074 consistent with resistance. In clinical studies, adverse events (AEs) were mild; no serious AEs were reported.

Although these results are promising, there are several questions that must be addressed before bNAb therapy can be a mainstay of HIV treatment, including development of treatment-emergent resistance, durability of viral suppression, and optimal bNAb combinations. Longer-acting formulations (NCT04319367), novel bNAb combinations (NCT03831945), and combinations with other therapies (NCT03619278, NCT03719664) are being investigated.

Although immunotherapy for HIV treatment is still under investigation, immunotherapy use in PLWH with cancer may allay concerns. Clinical trials have historically excluded PLWH because of the fear of unmasking opportunistic infection and interactions with antiretrovirals. Immunotherapy trials also have had to contend with the unknown effects of immunotherapy on T cells and questionable benefits in the setting of potential T-cell insufficiency.

 Recommendations in 2017 from the American Society of Clinical Oncology, the FDA, and Friends of Cancer Research advocate for including PLWH in immunotherapy clinical trials and provide eligibility guidance.

Generally, case reports and other studies have reported acceptable safety and tolerability to immunotherapy in various malignancies, such as anal, bladder, head, lung, and neck cancers; hepatocarcinoma; Kaposi sarcoma; melanoma; non-Hodgkin lymphoma; and renal cell carcinoma. Therapies have had no impact on the activation of opportunistic infections or HIV disease.

 Uses gaining support in PLWH include brentuximab-vedotin and rituximab for lymphoma,

 pembrolizumab, nivolumab, ipilimumab, and ipilimumab plus nivolumab for melanoma,

 and pembrolizumab and nivolumab for patients with non-small cell lung cancer (NSCLC).

As with all therapy, caution is warranted. A Veterans Health Administration case series describes outcomes with nivolumab in 16 PLWH with NSCLC, Hodgkin lymphoma, renal cell carcinoma, and off-label cancers as comparable with that of patients not infected with HIV, but larger studies are needed to confirm the 40% prevalence of immune-related AEs.

Ongoing immunotherapy studies in HIV-associated cancers include a phase 2 study of nivolumab in advanced NSCLC (NCT03304093), a phase 1 study of pembrolizumab in advanced gastrointestinal cancers (NCT02757391), a phase 1 study of ipilimumab and nivolumab in advanced solid tumors or classic Hodgkin lymphoma (NCT02408861), a phase 2 study of durvalumab in advanced cancer (NCT03094286), a study of pembrolizumab in various relapsed, refractory, and disseminated cancers (NCT02595866), and intralesional nivolumab for patients with Kaposi sarcoma (NCT03316274).

, is chief of the hematology oncology pharmacy at Tripler Army Medical Center in Honolulu, Hawaii.

, is a clinical pharmacy specialist in HIV and hepatitis C at Miriam Hospital in Providence, Rhode Island. 

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Antiretroviral therapy’s limitations lead to new efforts to treat the virus by neutralizing antibodies.