Early Emergence of Opportunistic Infections After Starting Direct-acting Antiviral Drugs in HIV/HCV-coinfected Patients

Juan Macías; Francisco Téllez; Antonio Rivero-Juárez; Rosario Palacios; Luis E. Morano; Dolores Merino; Antonio Collado; Lucio García-Fraile; Mohamed Omar; Juan A. Pineda; On behalf of the HEPAVIR, GEHEP and RIS-HEP07 study groups


J Viral Hepat. 2019;26(1):48-54. 

In This Article


Opportunistic infections are relatively common among HIV/HCV-coinfected patients receiving all-oral DAA combinations. Individuals suffering from those events may develop permanent sequelae or die as a consequence of them. Due to these, physicians managing HIV/HCV coinfection should be aware of paradoxical immunodepression-related reactivations of latent infections subsequent to starting DAA therapy.

We found unusual infections in patients with suppressed HIV replication with ART. Particularly, two AIDS-defining infections, PML and cryptococcal meningitis, emerged in subjects under ART. The patient who presented with PML had suffered from AIDS before, and his nadir CD4 cell count was <200 cells/μL. Infection by JC virus is asymptomatic, but in immunodepressed patients it can reactivate and lead to PML.[19] Reactivation of JC virus is usually seen in patients with <100 CD4 cells/μL. In anecdotal cases, PML can be observed with up to 200 CD4 cells/μL.[19] This case paradoxically took place in a patient that was on effective ART, with high CD4 cell counts, 12 weeks after achieving SVR12 with DAAs. The individual presenting with cryptococcal meningitis achieved undetectable plasma HIV RNA, without a parallel increase in CD4 cell counts, with ART. Cryptococcal meningitis can occur in patients starting ART as an immune reconstitution syndrome, as a consequence of the restoration of a cryptococcus-specific immune response. Infection with Cryptococcus neoformans can remain latent for years after initial exposure,[20] active disease may remain subclinical for some time in HIV-infected patients with advanced immunodeficiency, and clinical cryptococcosis may emerge for the first time after ART initiation.[21] The patient with cryptococcal meningitis was on ART for a period of time long enough to disregard the possibility of ART-induced immune reconstitution syndrome.

Other immunodepression-related infections were herpes infections and reactivations with severe presentations and a case with oral thrush. We did not observe HBV reactivations, but most study patients were under drugs active against HBV. Individuals who died due to complications of herpes infections showed CD4 cell counts lower than 200 cells/μL. However, plasma HIV RNA was undetectable in those patients. The temporal relationship of these cases with the use of DAAs and the lower risk of immunodepression-related infections in HIV-infected patients on stable ART, not receiving DAA combinations, raise the question of a potential causal link.

This study may have some limitations. First, this was a retrospective study, in which clinical records were reviewed to obtain data on events registered during a part of the follow-up. As such, some cases could have been missed and the incidence of events might have been underestimated. This is unlikely for immunodepression-related infections and severe bacterial infections, as severe outcomes, many of them requiring admission, are not easily overlooked. In addition, most HIV-infected patients are linked to tertiary care in Spain. They follow scheduled clinical visits, and in case of adverse outcomes, they usually seek medical attention at their infectious diseases unit. Second, we were able to compare the incidence of events reported herein with that of a control group of HIV-infected patients. However, the incidence of some minor non-AIDS events might have not been recorded in some cases, which might have led to an underestimation of the incidence of less severe infections in the control group. Comparisons with other studies are difficult because differences in key risk factors with the populations included in the studies where these data have been analysed preclude drawing reliable conclusions.[22]

There is no clear reason for the episodes of immunodepression-related infections and reactivations that we found in HIV-infected patients with suppressed HIV replication. It has been speculated that transient changes in immune status after HCV clearance with DAA combinations might increase the likelihood of VZV reactivations in HIV seronegative patients.[14] Supporting this, a down-regulation of intrahepatic interferon-stimulated genes has been found after the resolution of HCV infection with sofosbuvir plus RBV.[23] As in other conditions characterized by prolonged immune stimulation, resolution of infection and inflammation may be followed by a period of relative immunodepression.[24] This could explain the severe herpes, cryptococcosis and JC virus reactivations which we report herein.

In summary, HIV/HCV-coinfected patients can develop infections associated with immunodepression, even cases of AIDS-defining infections, with temporal relationship with the exposure to DAAs. Remarkably, the reactivation of immunodepression-related infections in the setting of treatment with all-oral DAA regimens occurs among patients with otherwise controlled HIV infection. Perplexing immunodepression-related reactivations of latent infections should be kept in mind by clinicians using all-oral DAA regimens in HIV/HCV coinfection. Studies aimed at identifying risk factors for the development of infections in patients living with HIV who receive treatment against HCV with DAA are necessary.