PI Perspective #39

November 2004     View PDF     En español

HIV Replication Capacity and Treatment Decisions

Researchers have known since the mid-1990s that some versions (strains) of HIV are less potent than others. Yet only recently have a number of studies sought to determine whether reductions or increases in HIV’s ability to reproduce (i.e. replication capacity) can be measured accurately and if these measurements could provide a useful tool for HIV research, and monitoring HIV progression and the effectiveness of therapy. While more research is needed, emerging data suggest that developing an effective test of HIV replication capacity is not only possible, but that such tests may become an important new tool in the fight against HIV disease.

What is replication capacity and why does it matter?
The term replication capacity—often used interchangeably with the term viral fitness—refers to how quickly a sample of HIV taken from your blood reproduces (replicates). The HIV taken from one person’s blood may reproduce more slowly or quickly than another person’s. Scientists have observed that the slower a person’s HIV reproduces, the less likely they are to have disease progression.

How to test for replication capacity
Currently, only one company in the U.S., ViroLogic,Inc., has a widely available test of HIV replication capacity (RC). Their RC test is included free of charge, whenever a doctor uses their combined phenotypic/genotypic HIV drug resistance test (PhenoSense GT). The RC test compares the rate at which HIV taken from your blood reproduces and compares this to the median rate at which a number of drug sensitive (wild-type) strains of HIV reproduce. The result is reported as a percentage, compared to the median wild-type at the bottom of the PhenoSense GT report. The makers claim that the results are about 95% accurate, so the actual percentage may be about 5% higher or lower than the number reported.

The company began offering the test in June of 2002, but only recently have data been published determining when and whether the results are at all meaningful.

What does the research show?
In 2001, researchers in San Francisco began to publish data on a group of people with HIV who maintained improved CD4+ cell counts and continued to do well clinically despite having persistently detectable HIV levels while on treatment. This stands in contrast to most people, whose CD4+ counts tend to fall soon after their viral load increases. Researchers sought to explain this observation, and further research concluded that reduced viral fitness, as measured by RC tests, is responsible.

Example of replication capacity percentage on the PhenoSense GT report.

Replication capacity (RC) indicates the ability of the virus to replicate in the absence of drug. Range represents 95% confidence interval around RC measurement. 100%=median RC of wild-type virus

In Italy, researchers studied a group of 18 people who were about to change anti-HIV therapy. Viral load, CD4+ count and HIV RC were tested at the time of the therapy change and one year later. People in the study fell into one of two groups; those who had a sustained increase in CD4+ counts to greater than 100 (immune responders) and those who did not (non-responders). Twelve of the 18 were immune responders and six were non-responders. Immune responders had a significantly greater reduction in HIV RC, compared to non-responders, regardless of their CD4+ cell count or viral load at study entry. Immune responders were also more likely than non-responders to have a specific mutation (M36I) in their virus.

A larger study of 189 people in San Francisco reported that reduced RC helps explain what is happening in people who have sustained increases in CD4+ cell counts even though HIV remains detectable. The study also showed that viral load was an important factor in predicting who might do well despite an incomplete virologic response to therapy. People who had viral loads below 10,000 were most likely to have continued good health.

A couple of very small studies also indicate that measuring HIV RC right after infection might be meaningful. The studies measured people’s HIV RC right after infection. None of the people were on anti-HIV drugs yet. The studies found that people infected with a version of HIV with reduced RC had less disease progression than those whose HIV reproduced more rapidly. Further research is needed to confirm these results in greater numbers of people. But the data so far imply that RC testing may become another useful tool to help people decide when and whether to start anti-HIV therapy.

Commentary
The role and value of RC testing is becoming increasingly clear. The data most strongly suggest that it can be a useful tool for people who have become resistant to most anti-HIV drugs and whose current regimen is no longer keeping HIV undetectable. There may be a number of reasons why a person may wish to stay on such a regimen, including good tolerability as well having too few potent drugs with which to construct a new regimen. The risk of sticking with such a regimen, however, is the potential for worsening CD4+ counts and the development of new drug resistance that could be even more harmful to potential future combinations. The use of RC testing, along with viral load tests, can now offer additional guidance about when and whether to switch regimens.

What remains less clear is the degree to which RC test results will be a useful measure of a person’s risk for disease progression when they’ve never taken anti-HIV drugs at all. The decision about whether to start anti-HIV therapy for the first time can be a difficult one. While there’s consensus that people whose CD4+ cell counts drop below 200 should definitely be taking anti-HIV drugs, there is much less agreement for people with CD4+ cell counts of 200–350. The U.S. Guidelines for the Use of Antiretroviral Drugs recommend that 350 should be the starting point for treatment, while others prefer to delay starting therapy until it falls below 200. Of course, there are other factors that must be considered, such as a person’s general health, viral load and how rapidly CD4+ counts are falling. However, it could be tremendously helpful if an RC test could more clearly identify those people most at risk of disease progression.

Like any new test, including viral load and resistance tests, the more people who use them and the more they undergo the scrutiny of research, the more useful they become. Replication capacity has promise, and future studies will certainly improve the test and our ability to use it.

GBV-C and HIV

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