Factors Associated With Treatment Initiation in HIV/HCV
Factors Associated With Treatment Initiation in HIV/HCV
We analysed factors associated with HCV treatment initiation between 2005 and 2011 in a large cohort of HIV/HCV-coinfected patients (n = 1048) managed in 17 French hospital units. One-third of the patients (n = 347) had been treated for HCV infection before their enrolment in the cohort (before 2005). Among the remaining, treatment-naïve patients, 194 (40.5%) of those with an indication for HCV therapy, as defined in French guidelines (see Methods), started treatment with peg-interferon plus ribavirin during cohort follow-up. [European guidelines for HCV therapy are similar to French guidelines, except that they include a lower HCV viral load threshold (< 400 000–500 000 IU/mL) for patients with genotype 1 infection, and do not deal with HCV genotype 4 infection [16]].
Patients with good adherence to HIV treatment (as perceived by their physician), patients who were childless, and patients with no history of cardiovascular disease or respiratory distress were more likely to be treated. When the analysis was restricted to the 339 patients with a formal indication for HCV treatment (fibrosis score ≥ F2), the only factor associated with HCV treatment initiation was good perceived adherence to HIV treatment.
Good adherence is critical for the efficacy of both anti-HIV and anti-HCV therapy. High levels of adherence are required to obtain sustained HIV suppression and long-term immunological and clinical benefits. The optimal level of adherence may differ according to the antiretroviral class, and should be better than 95% for nonboosted or boosted protease inhibitor (PI) regiments and at least 80% for nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens. Good adherence to HCV therapy is also required to achieve a sustained viral response, with a 'golden rule' of 80/80/80 (continued prescription of at least 80% of the interferon dose and 80% of the ribavirin dose for at least 80% of the planned treatment period). Patients who take > 80% of their peg-interferon alpha-2b plus ribavirin dosage for the entire treatment period have higher SVR rates. Adherence tends to be better for peg-interferon than for ribavirin, but decreases over time for both medications. Self-reported adherence is usually higher than that assessed by electronic measures, and the degree of discrepancy increases as treatment progresses.
In our study, 16% of patients did not receive HCV treatment because their physician considered their adherence to HIV treatment to be poor. In other studies, poor adherence or patient refusal was the reason for noninitiation of HCV treatment in 18% to 22% of patients. Specific interventions should be able to reduce this figure.
Social determinants may have a bearing on an individual's decision to begin anti-HCV treatment. In our study, parenthood was the only such factor associated with a lower rate of HCV therapy. Living with a partner was not a barrier to HCV therapy, but there was a trend in univariate analysis towards a higher rate of HCV treatment initiation in men (P = 0.08). The long duration of HCV therapy and side effects such as asthenia and depressive symptoms probably explain this barrier to HCV treatment in mothers. Newly available anti-HCV drugs with better efficacy, possibly allowing shorter treatment, may help to overcome this barrier. Housing status was not directly associated with HCV treatment initiation in our study, but patients who did not either own or rent their home were more likely to be considered as having poor adherence to HIV therapy by their physicians. Social interventions may help to ensure timely HCV treatment in this population.
Barriers to HCV treatment are more frequent in HIV/HCV-coinfected patients than in patients with isolated HCV infection, and mainly involve severe psychiatric disorders and ongoing alcohol use. We found that cardiovascular disease and respiratory distress were also barriers to HCV treatment initiation. Patients with a history of multiple treatments for depression were less likely to be treated when treated and nontreated patients were compared, whatever the indication (OR 0.39; 95% CI 0.17-0.88; P = 0.02) (data not shown).
Interestingly, despite the lower efficacy and poorer tolerability of HCV treatment in HIV/HCV-coinfected patients, we found no association between patients' negative perceptions of side effects or efficacy and treatment initiation. This could be a result of the fact that most patients (68%) had a formal indication for HCV treatment (Metavir score ≥ F2).
The main strength of our study is its large size: we enrolled 1048 HIV/HCV-coinfected patients managed in 17 hospital units throughout France, all with lengthy follow-up. This population was therefore probably adequately represented in the sample. The most important limitation of this study is probably our inability to determine the main reasons why physicians decided not to start HCV therapy. The number of different reasons cited by physicians for nontreatment has fallen over the years. HCV treatment is deemed less questionable: the lack of liver biopsy no longer seems to be a major barrier, and the number of contraindications to HCV treatment has also decreased. However, the numerous side effects associated with either peg-interferon or ribavirin, such as asthenia or depression, and/or the increase in the number of pills, which may result in poor adherence to therapy and therefore poor efficacy, could remain the reasons why physicians defer HCV treatment in some patients.
The second limitation of our study is that adherence to HIV therapy was only evaluated through the physician's personal perception and not by more objective methods such as self-reporting, pharmacy refill data or pill counting. However, in our study, perceived poor adherence to HIV therapy was associated with well-known factors such as alcohol consumption, homelessness, a history of injecting drug use, and depressive symptoms. The nadir CD4 cell count was also lower in patients with poorer adherence, reflecting a delay in linkage to care. In contrast, the rates of undetectable plasma HIV and CD4 cell counts were similar between patients who started HCV therapy and those who did not, maybe reflecting a hint of a discrepancy between the physician's personal perception and actual antiretroviral therapy adherence. Therefore, we presume that the physician's perception about adherence may be more related to perceived tolerability and potential risk of HCV treatment interruption. Developing expertise in HCV treatment and effective strategies for managing the side effects often encountered during HCV treatment might help to change physicians' personal perception of patients' poor adherence and help them to overcome the challenges of HCV therapy.
In conclusion, adherence to HIV therapy, as perceived by the patient's physician, seems to play a key role in the decision to prescribe treatment for HCV infection to HCV/HIV-coinfected patients. As a high level of adherence is required for new HCV PIs, which carry a higher risk of inducing resistance [24] and are possibly more toxic, developing the physician's expertise in HCV treatment, therapeutic education and adherence support might help to enable timely HCV treatment in patients with poor adherence to HIV therapy.
Discussion
We analysed factors associated with HCV treatment initiation between 2005 and 2011 in a large cohort of HIV/HCV-coinfected patients (n = 1048) managed in 17 French hospital units. One-third of the patients (n = 347) had been treated for HCV infection before their enrolment in the cohort (before 2005). Among the remaining, treatment-naïve patients, 194 (40.5%) of those with an indication for HCV therapy, as defined in French guidelines (see Methods), started treatment with peg-interferon plus ribavirin during cohort follow-up. [European guidelines for HCV therapy are similar to French guidelines, except that they include a lower HCV viral load threshold (< 400 000–500 000 IU/mL) for patients with genotype 1 infection, and do not deal with HCV genotype 4 infection [16]].
Patients with good adherence to HIV treatment (as perceived by their physician), patients who were childless, and patients with no history of cardiovascular disease or respiratory distress were more likely to be treated. When the analysis was restricted to the 339 patients with a formal indication for HCV treatment (fibrosis score ≥ F2), the only factor associated with HCV treatment initiation was good perceived adherence to HIV treatment.
Good adherence is critical for the efficacy of both anti-HIV and anti-HCV therapy. High levels of adherence are required to obtain sustained HIV suppression and long-term immunological and clinical benefits. The optimal level of adherence may differ according to the antiretroviral class, and should be better than 95% for nonboosted or boosted protease inhibitor (PI) regiments and at least 80% for nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens. Good adherence to HCV therapy is also required to achieve a sustained viral response, with a 'golden rule' of 80/80/80 (continued prescription of at least 80% of the interferon dose and 80% of the ribavirin dose for at least 80% of the planned treatment period). Patients who take > 80% of their peg-interferon alpha-2b plus ribavirin dosage for the entire treatment period have higher SVR rates. Adherence tends to be better for peg-interferon than for ribavirin, but decreases over time for both medications. Self-reported adherence is usually higher than that assessed by electronic measures, and the degree of discrepancy increases as treatment progresses.
In our study, 16% of patients did not receive HCV treatment because their physician considered their adherence to HIV treatment to be poor. In other studies, poor adherence or patient refusal was the reason for noninitiation of HCV treatment in 18% to 22% of patients. Specific interventions should be able to reduce this figure.
Social determinants may have a bearing on an individual's decision to begin anti-HCV treatment. In our study, parenthood was the only such factor associated with a lower rate of HCV therapy. Living with a partner was not a barrier to HCV therapy, but there was a trend in univariate analysis towards a higher rate of HCV treatment initiation in men (P = 0.08). The long duration of HCV therapy and side effects such as asthenia and depressive symptoms probably explain this barrier to HCV treatment in mothers. Newly available anti-HCV drugs with better efficacy, possibly allowing shorter treatment, may help to overcome this barrier. Housing status was not directly associated with HCV treatment initiation in our study, but patients who did not either own or rent their home were more likely to be considered as having poor adherence to HIV therapy by their physicians. Social interventions may help to ensure timely HCV treatment in this population.
Barriers to HCV treatment are more frequent in HIV/HCV-coinfected patients than in patients with isolated HCV infection, and mainly involve severe psychiatric disorders and ongoing alcohol use. We found that cardiovascular disease and respiratory distress were also barriers to HCV treatment initiation. Patients with a history of multiple treatments for depression were less likely to be treated when treated and nontreated patients were compared, whatever the indication (OR 0.39; 95% CI 0.17-0.88; P = 0.02) (data not shown).
Interestingly, despite the lower efficacy and poorer tolerability of HCV treatment in HIV/HCV-coinfected patients, we found no association between patients' negative perceptions of side effects or efficacy and treatment initiation. This could be a result of the fact that most patients (68%) had a formal indication for HCV treatment (Metavir score ≥ F2).
The main strength of our study is its large size: we enrolled 1048 HIV/HCV-coinfected patients managed in 17 hospital units throughout France, all with lengthy follow-up. This population was therefore probably adequately represented in the sample. The most important limitation of this study is probably our inability to determine the main reasons why physicians decided not to start HCV therapy. The number of different reasons cited by physicians for nontreatment has fallen over the years. HCV treatment is deemed less questionable: the lack of liver biopsy no longer seems to be a major barrier, and the number of contraindications to HCV treatment has also decreased. However, the numerous side effects associated with either peg-interferon or ribavirin, such as asthenia or depression, and/or the increase in the number of pills, which may result in poor adherence to therapy and therefore poor efficacy, could remain the reasons why physicians defer HCV treatment in some patients.
The second limitation of our study is that adherence to HIV therapy was only evaluated through the physician's personal perception and not by more objective methods such as self-reporting, pharmacy refill data or pill counting. However, in our study, perceived poor adherence to HIV therapy was associated with well-known factors such as alcohol consumption, homelessness, a history of injecting drug use, and depressive symptoms. The nadir CD4 cell count was also lower in patients with poorer adherence, reflecting a delay in linkage to care. In contrast, the rates of undetectable plasma HIV and CD4 cell counts were similar between patients who started HCV therapy and those who did not, maybe reflecting a hint of a discrepancy between the physician's personal perception and actual antiretroviral therapy adherence. Therefore, we presume that the physician's perception about adherence may be more related to perceived tolerability and potential risk of HCV treatment interruption. Developing expertise in HCV treatment and effective strategies for managing the side effects often encountered during HCV treatment might help to change physicians' personal perception of patients' poor adherence and help them to overcome the challenges of HCV therapy.
In conclusion, adherence to HIV therapy, as perceived by the patient's physician, seems to play a key role in the decision to prescribe treatment for HCV infection to HCV/HIV-coinfected patients. As a high level of adherence is required for new HCV PIs, which carry a higher risk of inducing resistance [24] and are possibly more toxic, developing the physician's expertise in HCV treatment, therapeutic education and adherence support might help to enable timely HCV treatment in patients with poor adherence to HIV therapy.
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