Treatment Regimens and Recommendations for HIV/HCV Coinfection

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Tenofovir disoproxil fumarate is associated with renal toxicity, the risk of which may be further increased if TDF is used with some oral DAA therapies for HCV.
Tenofovir disoproxil fumarate is associated with renal toxicity, the risk of which may be further increased if TDF is used with some oral DAA therapies for HCV.

Challenges in Treatment of HIV and HCV Coinfection

Coinfection with HIV and hepatitis C virus (HCV) is common. In the United States, up to one-third of those with HIV are coinfected with HCV and one-third of those with HCV are coinfected with HIV.1,2 The high prevalence of HIV and HCV coinfection is likely the result of shared modes of transmission for both types of infection, such as intravenous drug use, sexual contact, or mother-to-child transmission.3

“We need to be aggressively treating everyone with HCV, including and especially patients who are coinfected with HIV, because we know that patients who are coinfected are at higher risk for more rapid progression of liver disease,” Lisa Chirch, MD, FIDSA, Associate Professor of Medicine in the Infectious Diseases department at UConn Health in Connecticut, told Infectious Disease Advisor. Liver cirrhosis will develop in approximately one-third of patients with HCV and HIV coinfection within 20 years. Additionally, patients with coinfection are 3 times more likely to have progression to decompensated liver disease or cirrhosis than are patients with HCV infection alone.4

Previously, the only therapies available for HCV infection were pegylated interferon and ribavirin, which were often ineffective at disease control and poorly tolerated. The development of next-generation direct-acting antivirals (DAAs) for HCV has led to significantly improved sustained virologic response rates and better tolerability in people with both HIV/HCV coinfection and those with HCV alone.4 Consequently, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) guidelines for HCV treatment recommend that people with HCV and HIV coinfection be treated similarly to those with HCV monoinfection.5

Whereas the new oral DAAs make viral suppression of HCV an achievable goal in patients with HCV/HIV coinfection, the simultaneous use of HIV antiretroviral therapy (ART) presents new challenges regarding drug-drug interactions (DDIs). Infectious Disease Advisor spoke with Dr Chirch and with Oluwaseun Falade-Nwulia, MBBS, MPH, Assistant Professor of Medicine in the Infectious Diseases department at Johns Hopkins Medicine in Maryland, about the management of DDIs in patients receiving treatment for HIV and HCV coinfection.

Resources to Identify DDIs in HIV and HCV Regimens

“Providers who treat patients with HIV and HCV coinfection need to be aware of DDIs between HIV and HCV medications to prevent bad outcomes that are potentially avoidable,” Dr Falade-Nwulia said.

“We have so many options for HCV therapy now that we are in a position to treat any [patient coinfected with] HIV/HCV,” she added. However, with numerous potential HIV and HCV drug combinations, many DDIs are possible. Staying current on what DDIs may occur with all HIV and HCV medication combinations would be an impossible task.

Fortunately, several tools are available to aid clinicians in selecting HIV and HCV regimens that minimize DDIs. Dr Falade-Nwulia recommends consulting the user-friendly tables published in the AASLD/IDSA guidelines for the treatment of HCV infection. The tables can be found under the section, “Unique Populations: Patients with HIV/HCV Coinfection.”5 The tables are color coded to indicate which drug combinations are safe and which ones should be avoided because of DDIs.

Dr Chirch suggests additional resources, such as the HIV treatment guidelines issued by the US Department of Health and Human Services, which are updated at least once yearly and contain a section on drug-drug interactions.6 The AIDS Education & Training Center Program: Northeast/Caribbean has developed charts on DDIs for HIV medications as clinical support tools.7 In particular, Dr Chirch recommends the University of Liverpool's HEP iChart website and mobile phone app, which may be used to identify DDIs between HIV ART agents and any other medication.8 “It's really easy to use. I end up using this app very frequently,” she said. “If you plug in the medications that your patient is on and then plug in the medication that you want to use, it is difficult to miss any major problems.”

Important DDIs in HIV and HCV Treatment

Although resources are available to identify potential DDIs between HIV and HCV antiviral drugs, some general principles may help guide treatment selection. “The most recent iteration of the guidelines for the treatment of HIV recommend integrase inhibitor-based ART regimens as preferred regimens,” Dr Chirch said. DDIs are not as common with integrase inhibitors — which include dolutegravir, raltegravir, and elvitegravir — because they are metabolized by the uridine diphosphate glucuronosyltransferase pathway instead of by the CYP3A4 P450 system. However, Dr Chirch advised caution when using the integrase inhibitor elvitegravir because it requires boosting with cobicistat, which uses the CYP3A4 P450 enzyme, thus increasing the potential for DDIs.

According to Dr Chirch, some drug combinations should be avoided altogether. Protease inhibitors are widely used in the treatment of HCV and include grazoprevir, glecaprevir, and voxilaprevir. However, use of certain protease inhibitors for HCV with a boosted protease inhibitor for HIV that inhibits CYP3A4 P450 may elevate levels of the protease inhibitor for HCV, increasing the risk for liver toxicity in patients coinfected with HIV/HCV who already have some degree of liver disease. On the other hand, the ART agent efavirenz induces CYP3A4 P450, which may lead to lower levels of the co-administered drug, thereby potentially reducing its efficacy. “Efavirenz coadministration with most currently prescribed DAA regimens may be problematic, so that is one antiretroviral agent that you would consider switching off of if you were in that situation,” Dr Chirch said.

Tenofovir disoproxil fumarate (TDF), a nucleoside reverse transcriptase inhibitor commonly prescribed for HIV, is associated with renal toxicity. This risk may be further increased if TDF is used with some oral DAA therapies for HCV, according to Dr Falade-Nwulia. In particular, boosted protease inhibitor regimens may increase TDF exposure and raise the risk for renal toxicity. However, some combinations of TDF-based regimens plus oral DAAs for HCV present only a mild or moderate risk for renal toxicity, and therefore continuing treatment while closely monitoring kidney function may be an acceptable approach. A newer formulation of tenofovir, tenofovir alafenamide, is less nephrotoxic and has no DDIs with any of the oral DAA regimens for HCV.

Although no longer a preferred agent for HCV, ribavirin still sees use in combination with DAAs in patients who are treatment experienced or have liver cirrhosis. Using ribavirin-based regimens with some of the older nucleoside reverse transcriptase inhibitors — didanosine or zidovudine, for example — may lead to overlapping toxicities such as hepatic steatosis and lactic acidosis, and these combinations should be avoided, Dr Chirch said. Ribavirin can also cause dose-related hemolytic anemia, particularly when used with pegylated interferon. However, with newer agents available to treat HCV, anemia is now seen less frequently with ribavirin.

Managing DDIs in HIV/HCV Coinfection

The key principle to managing DDIs between HIV ART and HCV DAA therapy is to anticipate the problem before it occurs to prevent DDIs from happening, Dr Chirch said. In some cases, however, avoiding drug combinations that may lead to DDIs is not a feasible option. Some patients coinfected with HIV and HCV require a specific HCV regimen that is known to interact with their HIV regimen. If ribavirin must be used, for example, reducing the dose may help alleviate the risk for DDIs. The doses and dosing schedules of most other ART and DAA agents cannot be changed.

If the patient needs to be on a particular oral DAA regimen because of HCV genotype or severity of liver disease, their HIV ART treatment may need to be changed if the combination of regimens increases the risk for DDIs. “We are in a wonderful position now with so many options with ART that you can work with the patient to change their HIV regimen so that they are on a regimen that allows them to take an HCV oral DAA regimen,” Dr Falade-Nwulia said.

Before changing a patient's HIV regimen, the clinician needs to ensure that the new regimen will maintain virologic suppression of HIV. Dr Chirch recommends obtaining a thorough history of prior ART regimens that have not worked for the patient and results of resistance testing to avoid using ART agents that may be ineffective and result in suboptimal outcomes.

Changing a patient's HIV regimen also involves coordinated decision making with the patient. “You need to prepare the patient for the change,” Dr Falade-Nwulia said. “Sometimes [people with] HIV have been on their ART regimen for a really long time and they feel comfortable with this regimen.” Before starting HCV therapy, Dr Falade-Nwulia will switch the HIV regimen and monitor the patient for side effects and disease stability on the new regimen. She will then initiate HCV therapy once it becomes clear that the new HIV regimen is effective and the patient is comfortable with the treatment.

Modifying the HIV regimen to avoid DDIs with an HCV regimen is a complex and involved process. However, in a cohort study of 255 patients published in Hepatology, Dr Falade-Nwulia and colleagues found that only 30% of patients with HIV and HCV coinfection had to change their HIV regimens prior to starting DAAs for HCV.9 “Fortunately, the vast majority of patients with HIV/HCV coinfection do not require a switch in HIV therapy,” she said. 

References

  1. Scott JA, Chew KW. Treatment optimization for HIV/HCV co-infected patients. Ther Adv Infect Dis. 2017;4:18-36.
  2. Rice DP, Faragon JJ, Banks S, Chirch LM. HIV/HCV antiviral drug interactions in the era of direct-acting antivirals. J Clin Transl Hepatol. 2016;4:234-240. 
  3. Qadir MI. Hepatitis in AIDS patients [published online: October 13, 2017]. Rev Med Virol. doi: 10.1002/rmv.1956
  4. Poizot-Martin I, Naqvi A, Obry-Roguet V, et al; Hepadat'AIDS Study Group. Potential for drug-drug interactions between antiretrovirals and HCV direct acting antivirals in a large cohort of HIV/HCV coinfected patients. PLoS One. 2015;10:e0141164.
  5. AASLD, IDSA. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Updated September 21,2017. Accessed November 28, 2017.
  6. US Department of Health and Human Services, AIDSinfo. Clinical Guidelines. Updated November 28, 2017. Accessed November 28, 2017.
  7. AETC Northeast/Caribbean. HCV drug interactions Guides—includes interactions with HIV and primary care medications. Updated 2017. Accessed November 28, 2017.
  8. University of Liverpool. HEP drug interaction checker. Reviewed November 28, 2017. Accessed November 28, 2017.
  9. Falade-Nwulia O, Sutcliffe C, Moon J, et al. High hepatitis C cure rates among black and nonblack human immunodeficiency virus-infected adults in an urban center. Hepatology. 2017;66:1402-1412.
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