Systematic review of role of polymerase chain reaction in defining infectiousness among people infected with hepatitis C virus

Vertical transmission studies

In vertical transmission studies, which included mothers who were positive for hepatitis C by polymerase chain reaction and mothers who were negative (n=18), the percentage of mothers with positive results varied from 33% to 94%, with a pooled estimate of 54% (table 1). Three additional studies selected only those mothers with proved chronic hepatitis C infection.12 17 20 Among 903 children born to mothers positive for hepatitis C by polymerase chain reaction the rate of transmission of hepatitis C varied from 0% to 42%, with a combined rate of 6.2% (95% confidence interval 4.6% to 7.8%). In contrast, no case of transmission was reported among 735 children born to mothers negative by the reaction (0.0% to 0.4%) (table 1). Among positive mothers other factors which were reported to influence transmission were level of viraemia,17 18 20 25 28 coinfection with HIV,19 25 26 and method of delivery.19 The pooled transmission rate for hepatitis C from mothers positive for HIV and hepatitis C antibody was 15.8% (11.8% to 19.8%). In contrast, a transmission rate of 1.9% (1.2% to 2.6%) for hepatitis C was seen among children born to mothers who were seronegative for HIV or of unknown status. In five of seven vertical transmission studies in which measurement of hepatitis C viraemia was performed, transmission was associated with higher level viraemia.17 18 20 25 28 One study demonstrated a significantly higher transmission rate among vaginally delivered infants compared with infants delivered by caesarean section (32% v 6%)19 but showed no association between risk of transmission and breast feeding. Hepatitis C genotype and maternal alanine transferase activity did not correlate with risk of transmission in those studies where these factors were assessed.

Other transmission studies

The three studies examining transmission of hepatitis C from transplant donors positive for hepatitis C antibody to recipients negative for hepatitis C (table 2) gave a pooled transmission rate of 78% (72% to 94%) from donors positive by polymerase chain reaction compared with 0% (0% to 15%) from donors negative by polymerase chain reaction.32 33 34 Three retrospective studies of transmission after transfusion of blood components from donors positive for hepatitis C antibodies demonstrated a pooled transmission rate of 83% (74% to 92%) from donors positive by polymerase chain reaction compared with no definite case of transmission among 97 recipients of blood components from negative donors.35 36 37 One study found two recipients of blood component from donors negative by polymerase chain reaction to be positive for hepatitis C antibody (one negative by polymerase chain reaction, one positive), but pre-existing infection with hepatitis C could not be excluded as they had received multiple previous transfusions. Furthermore, the donor negative by polymerase chain reaction who corresponded to the recipient who was positive for hepatitis C antibody and positive by polymerase chain reaction had two further recipients who underwent testing, both of whom had no evidence of hepatitis C infection.

Although several studies have examined prevalence and incidence of hepatitis C among healthcare workers, only two studies have reported on hepatitis C antibodies and hepatitis C polymerase chain reaction status in source cases of needlestick exposures to healthcare workers (table 3).38 39 With combination of the results of these two studies, the transmission rates for hepatitis C after needlestick exposure to patients positive for hepatitis C antibody was 6.1% (2.3% to 9.9%) from patients positive by polymerase chain reaction and 0% (0.0% to 18.5%) after exposure to those negative by polymerase chain reaction.

Advances in technology

Rapid developments in polymerase chain reaction technology, however, have overcome many of these concerns. The sensitivity has been optimised through the use of nested primers based on the very highly conserved 5' non-coding region of the hepatitis C genome.42 Thus, improved standardisation of technology in conjunction with ongoing monitoring by national reference laboratories should limit the possibility of false negative results. The findings from our review also support the high sensitivity of hepatitis C polymerase chain reaction, at least in the setting of research laboratories, where specimens were generally tested in duplicate.

The main drawback of extreme sensitivity of polymerase chain reaction technology is an enhanced possibility of contamination and thus suboptimal specificity. This has been emphasised by an international quality assurance survey which detected false positive results from a large number of laboratories.43 Although increased vigilance to limit contamination and continued monitoring of specificity of the reaction are required, an occasional false positive result does not affect the finding of absent transmission of hepatitis C from patients negative for hepatitis C by polymerase chain reaction and the implications arising from such a finding.

The labour intensiveness of in house polymerase chain reaction technology, in particular nested reaction, has limited its availability. New methods such as nucleic acid amplification systemc (NASBA) and the Amplicor kit (Roche Diagnostic Systems, Basle, Switzerland), however, enable testing of large numbers of specimens in a single day and have equal sensitivity and specificity to the in house methods.44

Our review of published studies of hepatitis C transmission strongly supports the use of polymerase chain reaction testing for determination of infectiousness among people positive for hepatitis C antibodies. Even in situations where the hepatitis C inoculum was large, such as after blood transfusion, no definite case of transmission from a person positive for hepatitis C antibody but negative by polymerase chain reaction was documented.35 36 37

Implications for advice

Despite the improvements in polymerase chain reaction technology we have outlined, we would recommend that a person with hepatitis C is counselled on the basis of a persistently positive or negative hepatitis C polymerase chain reaction (at least two tests over a three month period) rather than a single assessment of polymerase chain reaction status. Even greater consistency would be required in a person receiving or having received interferon treatment because of the fluctuation in hepatitis C polymerase chain reaction status among this group. The greatest benefit would be in identifying those people with antibody to hepatitis C who have no biochemical or clinical evidence of chronic infection and who are persistently negative by polymerase chain reaction. This group of people could be counselled as to their non-infectiousness and most probable lack of chronic hepatitis C infection, with polymerase chain reaction having a similar role to that of hepatitis B virus core antigen in defining infectiousness and hepatitis B virus surface antigen in defining chronic infection.

Pregnant women, or women considering pregnancy, who are positive for hepatitis C antibody could be offered polymerase chain reaction testing to assist in determining their risk of transmitting hepatitis C to their infants; a woman persistently negative by polymerase chain reaction could be reassured that her risk of transmitting hepatitis C perinatally was essentially nil.

Determination of hepatitis C polymerase chain reaction status would also be useful after a needlestick exposure to blood or body fluid from a patient positive for hepatitis C antibody. If the source patient had no biochemical or clinical evidence of chronic hepatitis C infection and was negative by polymerase chain reaction, an exposed healthcare worker could be informed that the risk of acquiring hepatitis C was negligible. This information could allay considerable anxiety over the required 6-9 months before tests for hepatitis C are concluded.

The recent reports of hepatitis C transmission from two cardiothoracic surgeons to their patients has placed increased scrutiny on healthcare workers who are positive for hepatitis C antibody.45 46 In some places surgeons are already prevented from performing procedures likely to risk exposure if they are found to be infected.45 Hepatitis C polymerase chain reaction testing could be used to assess the potential for transmission from infected healthcare workers. While surgeons positive by polymerase chain reaction should be advised not to perform procedures that may lead to exposure, those surgeons who are persistently negative by polymerase chain reaction should not be required to undertake additional infection control measures.

Although transmission efficiency through sexual contact seems to be low, many people positive for hepatitis C antibodies are counselled to use condoms. A person found to be persistently negative by polymerase chain reaction could be advised that the risk of transmitting hepatitis C sexually was essentially nil.

Conclusions

In summary, it seems that there is virtually no risk of hepatitis C transmission in the absence of viraemia as detected by polymerase chain reaction. This finding has important implications with regard to counselling both those people at risk of transmitting hepatitis C and those exposed to infective sources. Additional investigation of transmission based on clinical stage of infection, level of viraemia, and genotype is required to define the level of infectivity further in various settings.