Concurrent Treatment of HIV, Disseminated Mycobacterium Avium Complex and HCV- Infection

Patients with HIV-infection diagnosed at late stages usually have significant immunosuppression and demand simultaneous antiretroviral therapy and treatment of opportunistic infections. The presence of HCV coinfection makes treatment even more challenging because of possible adverse effects and drug-drug interactions. HCV cure in such clinical situations not only prevents fibrosis progression, but can also enhance virologic and/or immunologic response to antiretrovirals and thus effective treatment of opportunistic infections. Thorough consideration of all existing diseases and drug interactions of the combined therapy makes simultaneous treatment of HIV, chronic hepatitis C, and opportunistic infections not only possible but the best way to improve outcomes in a complex clinical situation.


INTRODUCTION
Both the chronic hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) are significant public health challenges. Because of the shared modes of transmission, people at risk for HIV infection are also at risk for HCV infection. According to WHO, there were 71 million people living with chronic HCV infection and 37.9 million people living with HIV in 2018. The global estimate of burden of HIV-HCV co-infection was 2.75 million. Modern antiviral medicines can cure more than 95% of persons with hepatitis C infection. WHO's updated 2018 guidelines recommend therapy with pan-genotypic direct-acting antivirals (DAAs) for all persons with chronic HCV infection over the age of 12. 1 Access to HCV treatment is improving globally but remains limited. DAAs remain expensive in many high-and upper-middle-income countries, including the Russian Federation where the generic versions of these medicines are not licensed.
The rate of HIV infection is high in the Russian Federation. The disease is often detected in late stages when patients already suffer from one or more opportunistic infections. 106 560 new cases were detected in 2017 and this rate increases yearly according to the Federal Scientific and Methodological Centre for AIDS Prevention and Control. 2 Among patients under outpatient clinics observation in 2017, 22.3% had late stages of HIV-infection. 3 Parenteral drug use is still a common way of HIV transmission (18.9% of all newly diagnosed in 2017 according to official data). Therefore, coinfection with chronic hepatitis C is not rare and this poses additional challenges to treating such patients.  (Figs 1A, 1B). The abdominal MRI on June 9 detected enlarged lymph nodes in ligamentum hepato-mesenteric and mesenteric lymph nodes (8.5×9 mm, 18×15 mm), para-aortic lymph nodes were also involved (10×11 mm, 15×18 mm) (Fig. 2)   We started 24 weeks of sofosbuvir/velpatasvir according to EACS guidelines. 6

DISCUSSION
Disseminated MAC infection is a common problem in patients with advanced immunosuppression. This opportunistic infection can develop as a manifestation of immune reconstitution inflammatory syndrome (IRIS). 10 Our clinical case presents a classical course of the disease -a subacute development with flu like symptoms, diarrhea, massive involvement of abdominal and thoracic lymph nodes and insignificant involvement of pulmonary tissue.
According to the data, effective treatment of disseminated MAC infection in HIV patients is possible with a combination of a long course of multidrug therapy and an effective ART. This case shows a slower response to ART in the patient with chronic hepatitis C infection that may compromise successful treatment of such patients.
One of the most prominent benefits of hepatitis C treatment in HIV patients is a delay in the fibrosis progression. [11][12][13] At the same time, some studies show that after hepatitis is cured, patients enhance virologic or/and immunologic response to ART. 14 All these studies refer to the era of interferon-containing therapy which was restricted in HIV patients. 15 Interferon-free therapy facilitates treatment of HIV/HCV co-infected patients though there are some drug interactions between ART and medications against hepatitis C. The most significant interactions occur when combining direct-acting anti-HCV antivirals with non-nucleoside transcriptase inhibitors (NNRTI: efavirenz, nevirapine, and etravirine) as they can decrease concentrations of DAAs (resulting in a loss of efficacy and potential virological failure) by inducing cytochrome P450 enzyme system and P-glycoprotein. But still, NNRTI can be combined with sofosbuvir and sofosbuvir/ledipasvir without any dose adjustment. Boosted protease inhibitors (PI) also have significant interactions with anti-HCV antivirals. Nevertheless, sofosbuvir, sofosbuvir/ledipasvir and sofosbuvir/velpatasvir are eligible to be combined with PI. Integrase inhibitors have the most favourable interaction profile. Antiretroviral drugs switches may be performed to allow compatibility with DAAs.
Concerning opportunistic infections treatment, the most important drug interactions are connected with rifamycins -rifampicin and rifabutin that are contraindicated in combination with DAAs. With isoniazid and clarithromycin, weak interactions which can require dose adjustment are possible.

CONCLUSIONS
This clinical case demonstrates that the combined therapy of HIV, chronic hepatitis C, and opportunistic infections becomes possible after a thorough consideration of all drug interactions. Such simultaneous treatment can be the best way to improve outcomes in some clinical situations. All of the above stresses the need to expand the access of HIVpositive patients to the treatment of chronic hepatitis C with DAAs.