South Africa’s mass HIV testing programme has been a huge success over the past 10 years, with the country almost at the global target of 95% of people with HIV knowing their status.
This success has largely been built on the use of many millions of rapid HIV tests, writes Amy Green in Spotlight, however, while fourth-generation tests might be even more effective, government appears hesitant about them because of their “stability” and pricing.
The UNAIDS targets for 2030 are that 95% of people living with the virus know their status, 95% of those who are diagnosed are on treatment, and 95% of those on treatment are virally suppressed. Minister of Health Dr Joe Phaahla said South Africa has reached 94, 78, 89, respectively.
Now, fourth-generation rapid HIV tests and a new testing algorithm might push the country even closer to the 100% mark – where effectively all people with HIV have been identified and diagnosed.
Rapid tests
“Rapid tests are the main tool used to identify people with HIV,” says Professor Adrian Puren, executive director of the National Institute of Communicable Diseases (NICD).
This is because roughly 80% of the population is uninsured, relying on the public health sector. Rapid HIV tests can be done anywhere, and don’t require sophisticated laboratory infrastructure or the high-level expertise of a lab technician or pathologist.
They are designed to be used by most people, yet not just anyone can perform them. Some training is involved but, thereafter, most lay people can conduct the tests accurately and safely.
They are, therefore, cheaper than lab-based tests, which is necessary in our public sector where, says the National Department of Health’s Dr Thato Chidarikire, between 15m and 18m screening tests are conducted annually. Chidarikire is the director of HIV Prevention Programmes at the department.
Additionally, rural and outlying areas far from established laboratories are well-served by the rapid testing programme. Rapid tests deliver a quick result, usually within 30 minutes.
Lab-based tests
“In the public sector, if a patient ends up in a hospital or has a suspected HIV infection that was not identified with rapid tests, they may be tested using the laboratory system,” says Puren. Public sector laboratory testing is run by the National Health Laboratory Service. Laboratory-based HIV tests used for diagnostic purposes are usually enzyme-linked immunosorbent assays (ELISA).
The private sector does not routinely use rapid tests, says Professor Eftyhia Vardas, a professor of medical virology at the University of Stellenbosch and head of virology at Lancet Laboratories, Johannesburg.
While there are advantages of rapid tests for the public sector, she said these are not used routinely in the private sector where the drawbacks are considered significant (and avoidable via lab-based testing) and where there aren’t the same cost constraints.
Her department pays between R7 and R8 for a rapid test. At Lancet laboratories, the cost of two ELISA tests is between R280 and R300.
“There are variables with rapid point-of-care tests like how frequently the staff at clinics do competency tests. We check competency monthly to ensure our lab technicians haven’t forgotten anything. The competency of whoever’s reading the test can have an impact on the end result,” she says.
Additionally, rapid tests have a high sensitivity rate that can result in more false positives than lab-based tests.
HIV tests have to conform to guidelines on sensitivity and specificity. The sensitivity refers to the percentage of results that will be accurately positive when HIV is present. High sensitivity means the test is geared to never miss a positive case and thus more likely to cause false positives. Specificity refers to the percentage of results that will be accurately negative when HIV is not present. High specificity is likelier to cause false negatives.
World Health Organisation guidelines require rapid tests to have minimum sensitivity rates of 99% and minimum specificity rates of 98%, but this does not eliminate all inaccuracies.
“Rapid tests have built-in high sensitivity because they are designed to not miss a case but this does, unfortunately, result in some false positives,” says Vardas.
Instead, at the Lancet laboratories, two ELISA tests are used when testing for HIV – a screening test followed by a confirmatory test, if it’s a positive result.
However, Puren tells Spotlight it’s not necessarily the higher sensitivity of the rapid tests themselves that results in higher false positive rates, but that there are uncontrollable factors around rapid testing in the field, compared with a lab environment.
Two-test strategy
Puren says there are many layers of protection in the current system, ensuring tests give as accurate results as possible.
A two-test strategy, in line with WHO guidelines, is followed by both the public and the private sector. The first is called a screening test and Puren says a rapid test with a high sensitivity rate is usually used, with the aim of not missing a positive case. The second is called a confirmatory test – usually a product with higher specificity.
Despite this, false negatives and false positives do occur and are likelier with rapid tests. Vardas says there are cases of people being initiated on to HIV treatment who do not actually have HIV.
SA is preparing to move to a three-test strategy recommended by the WHO in areas with test positivity rates below 5%. While Puren says we have high rates in some contexts (as high as 30%), there are places where positivity rates are closer to this 5% mark, where most people getting tested are not HIV-positive.
Puren said the rate of false positives increases when the positivity rate falls, so a third confirmatory test must ensure misdiagnosed cases are minimised.
Chidarikire tells Spotlight the Health Department will implement a three-test strategy in the upcoming national tender for rapid tests. The current tender expires in June 2023.
About 10% of all HIV tests in the private sector are positive so there is no need for them to move to a three-test strategy. But other factors are in place to mitigate misdiagnosis and improve test accuracy.
Test approval
All HIV tests must have WHO prequalification status, meaning they have undergone a rigorous approval process.
Furthermore, they must be licensed by the South African Health Products Regulatory Authority (Sahpra). Head of medical devices at Sahpra Dr Dimakatso Mathibe said they do not evaluate diagnostic tests themselves but use a reliance pathway to award licences – relying on the approval the device has received in other jurisdictions, including the US Food and Drug Administration (FDA) and the European Medicines Agency.
When awarding the national tenders for HIV tests, she says, Treasury and the National Department of Health confirm with Sahpra whether the product is fully licensed.
Training of testers
Research shows that while false positives and false negatives “should be anticipated” with rapid diagnostic tests, the risk is low when using the correct testing strategies (like the two-test strategy in high-prevalence areas like South Africa).
Most misdiagnoses have occurred due to suboptimal testing strategies, poor management of supplies (the physical tests weren’t managed correctly), user errors – including difficulty interpreting weak reactive lines (faint lines appearing on test strips), and, finally, retesting people on HIV treatment. This means most misdiagnosed cases aren’t due to the actual test quality.
The department now has an ongoing training programme, and Chidarikire says all nine provinces have Regional Training Centres and “implementers should be trained every two years”.
Third-generation versus fourth-generation tests
An obstacle in all HIV programmes is that many tests are unable to detect HIV immediately after infection: there is a window period from infection until a test can diagnose infection.
Older tests had a window period of about six months or more. Third-generation tests, the current rapid tests used in the public sector, test only for antibodies produced by the body in response to an infection.
Fourth-generation tests detect both antibodies and the p24 antigen – which is part of the virus and induces the body to manufacture antibodies. The p24 antigen appears in the blood a few days before any antibodies can be detected. Therefore, fourth-generation tests shorten the window period slightly.
Both the private and public sector lab-based programmes already routinely use fourth-generation tests that detect both antibodies and antigens. The US Centres for Disease Control and Prevention (CDC) says a lab-based fourth-generation test can detect HIV from between 18 to 45 days after infection.
HIV can sometimes be identified earlier – as soon as 14 days after infection.
Professor Francois Venter, head of Ezintsha at the University of the Witwatersrand, said the window period can be as short as 10 days in some cases.
The CDC says rapid third-generation tests can detect HIV as soon as 23 days after infection but sometimes need up to 90 days. Rapid fourth-generation tests can detect HIV as soon as 18 days after infection but may also take as long as 90 days sometimes.
Fourth-generation rapid tests a good option?
This difference may seem small – five days between rapid third and fourth-generation tests, however, as Venter says, people who are acutely infected with HIV are also the most infectious. Up to 50% of all HIV transmission is from people acutely infected with HIV – who have been very recently infected with the virus.
Furthermore, Puren says fourth-generation rapid tests can help identify breakthrough infections for people taking PrEP, which, if taken as prescribed, is incredibly effective at preventing HIV infection, but there are rare cases of breakthrough infections acquired while on PrEP.
Strains of HIV resistant to commonly used antiretroviral medicines are difficult and expensive to treat.
Future plans
Chidarikire says the national Health Department has no plans to introduce fourth-generation rapid tests into the public sector mass testing programme.
“At the moment, the reason why SA is not using fourth-generation tests is because of their stability and performance,” she says. While third-generation rapid tests have higher than 99% sensitivity and specificity rates, available fourth-generation rapid tests don’t perform as well.
For example, the Alere Determine HIV-1/2 Combo, the only licensed fourth-generation rapid test in SA, has a sensitivity rate of 95%. Specificity was much higher and comparable to third-generation tests.
Additionally, said Chidarikire, “Fourth generation tests vary from R300 to more than R700 or more for a pack of 20 or 25 single tests”.
However, the price “should improve via bulk procurement” if it were put on tender.
Currently, the WHO guidance does not recommend this option for our setting but this may change if the tests’ performance improves.
However, Venter believes these debates equate to “navel-gazing” and if there is a potential benefit to including fourth-generation tests in our programme, it should be done.
Spotlight article – In-depth: Should SA invest in the latest HIV tests? (Creative Commons Licence)
See more from MedicalBrief archives:
Young people receiving HIV treatment in SA increase 10-fold
Half of the people in SSA ‘do not know their HIV status’
False positive results a concern in rapid diagnostic tests
HIV infection despite apparently adequate adherence to PrEP
7 graphs that tell SA’s HIV story