Our main findings regarding SN-HCV among PLWH were: 1) we identified its association with a relatively sparse number of clinical factors (history of IDU, elevated ALT, low platelets, black race, and undetectable HIV RNA); 2) we present a clinically useful method of summing clinical factors that may simplify identification of SN-HCV; 3) we found that SN-HCV prevalence varied by site prevalence of HCV; and 4) we present a model that takes into account both the number of risk factors and site SP-HCV prevalence in predicting SN-HCV.
IDU is a well-recognized risk factor for HCV infection among HIV-infected individuals.2, 3
Our study confirms the earlier reported association between a history of IDU and SN-HCV.14, 16
However, in contrast to our findings, George et al reported that SN-HCV infection was more common from mucosal or sexual compared to parenteral exposure.17
Elevated serum ALT levels indicate hepatocellular damage.18
Similar to our study, Chamie et al reported an association between elevated ALT levels and SN-HCV viremia in their cohort14
but no link was found in several other studies.15-17
Thrombocytopenia is associated with SP-HCV and with HIV infection.19
We believe that this is the first study to find an association between SN-HCV and thrombocytopenia among PLWH. We also found higher rates of SN-HCV in Blacks than in other races and this may be related to a higher HCV prevalence in Black race (3.2%) as seen in the NHANES III cohort.1
People who have had advanced immunosuppression may have persistently abnormal humoral immunity, resulting in the absence of antibodies to pathogens such as HCV. Support for this hypothesis comes from prior reports that people with SN-HCV had lower CD4+ T-cell counts than those with SP-HCV infection.14, 15, 17
CD4+ T-cell count nadirs in CHARTER are self-reported and may be susceptible to recall bias. To overcome this, we also included other measures that might reflect a history of advanced immunosuppression: current (measured) CD4+ T-cell count, AIDS diagnosis, current antiretroviral use, and HIV RNA levels in blood, an indicator of antiretroviral use. However, like Hall et al16
, we did not find an association between immunosuppression or use of antiretroviral drugs and SN-HCV, although we did find an association with undetectable HIV RNA levels in plasma. The explanation for this finding may be the relatively advanced immunosuppression of our group. While most subjects achieved some degree of immune recovery (CD4+ T-cell counts at the assessment visit exceeded the nadir CD4+ T-cell count by a mean of 232 cells/μL), the selected subgroup was more likely than the CHARTER cohort as a whole to have worse immunosuppression, whether estimated by nadir CD4+ T-cell counts, current CD4+ T-cell count, or AIDS diagnosis. In fact, we saw a trend in which subjects who had undetectable plasma HIV RNA levels had slightly lower nadir CD+ T-cell counts (mean 122 vs. 154/μL, p = 0.07). Thus, in this analysis, an undetectable HIV RNA level in plasma may be a surrogate for a history of more advanced immunosuppression and persistently impaired antibody production. Antiretrovirals themselves are not known to suppress HCV viremia or antibody production.
To optimize the clinical relevance of our model, we compared the number of clinical variables to rates of SN-HCV. A threshold of 3 clinical variables detected most of the SN-HCV cases but had a higher false negative rate that would increase the cost of screening with an HCV RNA assay. On the other hand, a threshold of 4 clinical variables missed some SN-HCV cases but would result in lowering screening costs. The cost of under-diagnosing SN-HCV infection could result in higher ultimate costs because of progressive liver disease in the undiagnosed individuals and perpetuation of transmission. The predictive ability of the model was further improved by including HCV prevalence at each site, suggesting that the optimal threshold for testing seronegative PLWH for HCV viral load should be tailored based on HCV prevalence in the population.
The cost savings of our selection criteria can be significant but will depend on the clinical variables cutpoint used and the prevalence of SN-HCV in the population tested. For example, in our cohort of 200 HIV+ individuals, the cost of screening everyone by HCV RNA would be $25,000 ($125 per PCR assay). Using a cutpoint of 4 clinical variables to test selected individuals would result in a much lower cost of $4,500 (80% saving). This approach would capture 16 people with SN-HCV in the 37 people that we test but will miss 10 people with SN-HCV in the 163 people not tested. A cutpoint of 3 would increase the sensitivity identifying 22 people with SN-HCV but also increase the cost to $10,750 (57% saving).
The analysis has important limitations. First, the selection of the subgroup based on clinical variables associated with HCV limits generalizability of the findings. This selection approach was used intentionally to determine if it would improve the efficiency of case finding compared with historical reports. Second, our quantitative assay to measure HCV RNA in serum we may have missed some SN-HCV people with low viremia. There are methods to improve the sensitivity of HCV PCR and include ultracentrifugation of serum samples20
and use of whole blood17
or liver tissue specimens21
but these methods are either not commercially available or use specimens that are not readily accessible. Third, 16 of the 26 SN-HCV individuals had no follow-up. As a result, we cannot confidently exclude acute infection with subsequent seroconversion as an explanation for SN-HCV in all subjects. However, the likelihood of this is low as shown by a longitudinal study of early HCV infections in PLWH of whom 60% became seropositive at 3 months and 95% at 1 year.22
We found that only 20% of the individuals who did have follow-up seroconverted over nearly a year of follow-up. Also, there was no significant difference in the characteristics of the subjects with or without follow-up.
In conclusion, we found that a combination of clinical risk factors identified those at a higher risk of HCV viremia among HCV seronegative PLWH. Given the characteristics of our cohort, our findings may be most relevant to patients who have had advanced immunosuppression and have achieved some degree of immune recovery in response to ART. However, if validated in a less selected cohort, this approach could provide a simple screening method to identify patients who might benefit from further HCV assessment.