Treatment of HCV in the setting of HIV coinfection
Simultaneous infection with HIV and HCV is associated with an increased rate of progression to liver cirrhosis, increased risk of HCC and increased mortality,84 even in those achieving full HIV virological suppression with antiretroviral treatment (ART) for HIV.85,86 Eradication of HCV can prevent these complications, and people with HCV–HIV coinfection should be prioritised for treatment of HCV. In contrast to IFN-containing regimens, IFN-free DAA regimens for HCV are just as effective in the setting of HCV–HIV coinfection as they are in HCV mono-infection.87-92 Drug–drug interactions, cumulative drug toxicities and increased pill burden are the main considerations when planning HCV treatment in people living with HIV. It is also important to note that thrombocytopaenia may occur secondary to HIV infection rather than portal hypertension; this may influence interpretation of APRI and FIB-4 serum markers for liver fibrosis staging. Serum bilirubin levels may be elevated by ARTs that inhibit biliary transporters. People with HIV–HCV coinfection should be cared for by a multidisciplinary team with experience in managing both viral infections.
Prevention and screening tests for HCV in people who are HIV-positive
HCV and HIV share common routes of acquisition. The risk of sexual (permucosal) transmission of HCV in people with HIV is increased, and the majority of sexual transmission of HCV occurs in HIV-positive people, particularly in men who have sex with men (MSM). High-risk practices include fisting, sharing sex toys, group sex and concurrent use of recreational drugs, particularly drugs absorbed through the mucosa.93 Unprotected anal intercourse alone has been associated with an increased risk of HCV transmission.
Education and discussion about harm reduction strategies to prevent parenteral or sexual transmission of HCV are important. HIV pre-exposure prophylaxis has no efficacy in preventing the transmission of HCV. Those wishing to minimise their exposure risk of HCV should be advised of safer sex practices, including condom use. Access to peer and social support; psychological, alcohol and drug counselling; and information about preventing transmission of HIV and HCV by parenteral and sexual routes and avoidance of HCV reinfection should be provided
All people who are infected with HIV should be tested for HCV,94 and all HCV-positive people should be tested for HIV. It is recommended that people who are HIV-positive should be screened with HCV serological testing annually.95 Those who are at high risk of HCV acquisition should be rescreened using 3–6-monthly liver function tests, with HCV RNA PCR performed in the setting of an unexplained rise in transaminase levels. HIV-positive individuals who achieve SVR after DAA therapy remain at risk of reinfection with HCV, and should continue to be screened with annual HCV RNA PCR and 3–6-monthly liver function test monitoring.
Antiretroviral treatment in people with HIV– HCV coinfection
ART is now recommended for all people with HIV irrespective of CD4+ cell count.96 HIV ART-naive people with HIV–HCV coinfection should have an ART regimen selected that will minimise drug–drug interactions with HCV medications and minimise potential liver toxicity. HIV should be controlled before HCV treatment, particularly in those with advanced HIV immunosuppression (CD4+ count, < 200 cells/mm3). HIV-related opportunistic infections should be treated before initiation of HCV treatment. Treatment of people with a CD4+ cell count greater than 500 cells/mm3 may be deferred until HCV treatment is completed, to avoid drug–drug interactions. ART should not be switched for people who are on a stable regimen unless an unavoidable and unmanageable drug–drug interaction is identified, because switching ART in HIV virologically suppressed patients has a risk of HIV virological failure.97
HCV treatment in people with HIV–HCV coinfection
The treatment regimens for HCV in people with HIV are the same as those used for HCV mono-infection and, as noted, the response rates are equivalent.87-92,98 Selection of DAA therapy for people with HIV–HCV coinfection should be as for HCV mono-infection, with the important caveat that ART increases the likelihood of clinically significant drug–drug interactions. A careful assessment of potential drug–drug interactions between DAAs and ART and drugs prescribed to manage HIV-related complications and comorbidities should be made before commencing HCV treatment, using the University of Liverpool’s Hepatitis Drug Interactions website (www.hep-druginteractions.org). Caution is warranted even for combinations of HIV ART and HCV DAAs where a specific drug–drug interaction issue is not expected or reported, as further information on interactions is likely to emerge. Due to extensive drug–drug interactions, tipranavir should be avoided with concurrent HCV DAA therapy. Caution should also be exercised in selecting the 8-week regimen of sofosbuvir–ledipasvir for individuals with Gt 1 HCV and HIV coinfection and an HCV viral load less than 6 000 000 IU/mL due to the lack of high-quality efficacy data in this population; cirrhosis and advanced fibrosis should be definitively ruled out using transient elastography before selecting this regimen.
Drug interaction studies of sofosbuvir with antiretroviral drugs (including efavirenz, tenofovir, emtricitabine, rilpivirine, ritonavir-boosted darunavir, and raltegravir) in uninfected individuals have not identified any clinically significant interactions.99 Sofosbuvir is not recommended for use with tipranavir because of the potential of tipranavir to induce P-glycoprotein.
Tenofovir disoproxil fumarate (TDF) exposure is increased when coadministered with ledipasvir, particularly when the ART regimen also includes efavirenz–emtricitabine or rilpivirine–emtricitabine. The effect may be further amplified when the ART regimen also includes elvitegravir–cobicistat or an HIV protease inhibitor boosted with ritonavir. Caution should be exercised with the combination of TDF and ledipasvir, with frequent monitoring for tenofovir-associated kidney injury, and if the ART regimen also includes ritonavir or cobicistat boosting, an alternative to ledipasvir should be considered.
Tenofovir alafenamide (TAF) has recently been PBS-listed for the treatment of HIV in Australia (TAF is not yet listed for the treatment of HBV). As tenofovir pharmacokinetics are lower with TAF relative to TDF based on data in healthy volunteers, TAF may be an alternative to TDF during sofosbuvir–ledipasvir treatment for patients who take elvitegravir–cobicistat or ritonavir-boosted HIV protease inhibitors as part of their ART. The combination of ledipasvir with TAF is not expected to cause kidney injury.
Drug interaction studies with velpatasvir–sofosbuvir have been performed in HIV and HCV seronegative volunteers. As with ledipasvir–sofosbuvir, tenofovir exposures are increased when velpatasvir is coadministered with TDF, which may be problematic for individuals with eGFR values of less than 60 mL/min or in those receiving ritonavir- or cobicistat-containing ART with tenofovir. The use of TAF in place of TDF should be considered in those requiring ritonavir- or cobicistat-containing ART — the combination of velpatasvir with TAF is not expected to cause kidney injury. If the combination of TDF with a ritonavir- or cobicistat-containing ART is required, renal parameters should be checked at baseline and regularly thereafter while taking sofosbuvir–velpatasvir.
Velpatasvir exposures are significantly reduced with efavirenz, and this combination is not recommended. Etravirine has not been studied with sofosbuvir–velpatasvir but is also not recommended. Indirect bilirubin level increases have been reported when sofosbuvir–velpatasvir was used in patients taking atazanavir–ritonavir, but these changes are not considered clinically significant.
Daclatasvir is available in both 60 mg and 30 mg formulations to manage drug–drug interactions. When administered concurrently with efavirenz, the dose of daclatasvir should be increased to 90 mg daily. Etravirine and nevirapine also decrease daclatasvir levels, requiring an increased dose, but as the effect has not been studied, these combinations should be avoided where possible. No daclatasvir dose adjustment is needed with rilpivirine. HIV protease inhibitors used without pharmacological “boosting” by ritonavir generally do not require dose adjustment of daclatasvir. However, when atazanavir, fosamprenavir, indinavir or saquinavir are used in combination with ritonavir, the daclatasvir dose should be reduced to 30 mg daily. The dose of daclatasvir should also be decreased to 30 mg daily when used with cobicistat. There is no need for daclatasvir dose adjustment when used with lopinavir–ritonavir or darunavir–ritonavir.
Paritaprevir–ritonavir, ombitasvir and dasabuvir
Given extensive drug–drug interactions, the combination of PrOD should be avoided in those whose ART regimen includes non-nucleoside reverse transcriptase inhibitors or HIV protease inhibitors apart from atazanavir, in which case ritonavir should be omitted from the ART regimen. Further, due to the inclusion of ritonavir in the DAA regimen, all people treated with this combination should be receiving suppressive HIV therapy.
Elbasvir plus grazoprevir
Significant drug–drug interactions preclude the concurrent use of elbasvir plus grazoprevir with many antiretroviral agents. This regimen is not suitable for use with HIV protease inhibitors. All HIV protease inhibitors inhibit OATP1B, leading to substantial increases in the plasma concentration of grazoprevir and increasing the risk of late elevations in ALT level. Coadministration with the quadruple-combination HIV agent elvitegravir–cobicistat–emtricitabine–TAF has not been studied, but should be avoided because the same antiretroviral combination using TDF resulted in substantially increased grazoprevir exposure. Elbasvir plus grazoprevir should not be coadministered with non-nucleoside reverse-transcriptase inhibitors, which will decrease elbasvir–grazoprevir exposure (proven in the case of efavirenz; a potential concern in the case of nevirapine and etravirine). Rilpivirine is the exception — no significant effect on elbasvir–grazoprevir exposure was seen with concomitant rilpivirine administration.40
Ribavirin-containing regimens should be avoided in people treated with zidovudine, stavudine or didanosine and may have increased risk of toxicity when used with abacavir and atazanavir.