In the past decade, the measurement of viral load, or the number of copies of HIV virus circulating in the bloodstream, has emerged as a useful complement to the CD4 count in guiding highly-active antiretroviral therapy (HAART). Viral load tends to be high during the initial infection with HIV, but the immune system quickly rallies to suppress replication of the virus, and the viral load drops. However, as HIV infection progresses towards acquired immunodeficiency syndrome (AIDS), CD4 counts drop, and viral load steadily increases.
The earliest studies suggested that the higher the viral load, the quicker the progression to AIDS. With HAART, viral load can be reduced to levels that cannot be detected by laboratory tests. However, viral load increases as HIV becomes resistant to therapy, indicating that a change in medication regimen should be considered for continued suppression of HIV infection.
Viral load is usually measured via a routine blood draw, using a test called reverse transcriptase polymerase chain reaction (RT-PCR). This is a biochemical reaction that amplifies the genetic material (or RNA) of the HIV virus so that it can be measured through special techniques. The standard RT-PCR test can detect no lower than 400 copies of the virus per milliliter of blood, while an ultra-sensitive version of the RT-PCR test can detect as few as 50 copies per milliliter. Currently, the RT-PCR test is the only method that is approved by the Food and Drug Administration (FDA) in the United States to measure viral load.
Two other kinds of tests can be used to measure viral load, and are sometimes used in other countries or in clinical trials. One test uses measurement of "branched DNA" (bDNA) to measure viral load and can also detect as few as 50 copies per milliliter of blood. The other test is called "nucleic acid sequence based amplification" (NASBA) and can detect no lower than 100 copies per milliliter. Most people have similar viral load levels when measured by these different methods. However, in some cases, the levels can vary between tests by 2-3-fold. Thus, it is important to use the same method when tracking viral load over time and not to compare results from two different testing methods.
The use of viral load in the management of HIV infection is a rapidly changing and controversial field, and current guidelines for its use will almost certainly change in the future. Determination of viral load is most useful when used in conjunction with CD4 counts. While the appearance of opportunistic infections (OIs) seems to correlate better with lower CD4 counts than with increases in viral load, viral load is of use primarily in two situations: early detection of new HIV infection, and determination of the response to medical therapy.
Diagnosis of new HIV infection is confirmed by the detection of antibodies against the HIV virus in an infected individual. However, this antibody may not be present in the bloodstream for up to 6 months, often delaying diagnosis of HIV infection and causing considerable psychological stress. This period of uncertainty is often called the "window period", in which antibody tests may be negative but the virus is actively replicating at high levels within the body. Rather than waiting for the six-month period to pass before re-testing, viral load measurement can confirm active replication of the virus within the body (usually greater than 200,000 copies per milliliter in an early, new infection), thereby establishing or ruling out a diagnosis of HIV infection.
Viral load measurements are also useful in monitoring the response to antiretroviral therapy. While changes in CD4 counts lag after initiation of therapy or changes in medications, changes in the viral load are seen more rapidly and may be a better indicator of the risk of developing OIs. After starting HAART, viral load is expected to decrease by three- to ten-fold over the next four to eight weeks and should be less than 500 copies per milliliter at four to six months, preferably below the range of detection of the laboratory tests. If these levels are achieved, viral load is commonly measured every 3-4 months to determine if the response is sustained. If the viral load does not fall below 500 copies per milliliter at four to six months, treatment is considered to be ineffective and the usual recommendation is to change therapy.
Similarly, if the viral load suddenly increases while on a stable HAART regimen, it may represent emerging HIV resistance to the current drug therapy. However, small variability in viral load between measurements is common (resulting from natural variations in time or from error ranges in laboratory tests) and does not necessarily represent resistance to drug therapy. As a result, a change in viral load of at least three-fold usually occurs before medication changes are considered. Because ten-fold increases in viral load can occur in the context of vaccinations or any illness (e.g., colds, the "flu", or herpes outbreaks) and persist for one month or more, viral load should not be measured during this time period.
More controversial is the use of viral load in deciding when to initiate therapy. HAART is commonly initiated based on the CD4 count or the appearance of OIs. However, some people advocate starting HAART in asymptomatic people with CD4 counts greater 300 with higher viral loads (>10,000-55,000 copies per milliliter), believing that HIV suppression may be more difficult if viral loads are allowed to increase to even higher levels. While the research regarding this concept is still evolving, use of viral load for this purpose is not currently standard practice.
The measurement of viral load clearly has vital importance in assessing the response to drug therapy and determining when medication changes should be implemented. As a result, differences in viral load between different subpopulations, including people of different ethnicities, genders and geographical locations, may have significant implications for the management of HIV infection.
Recent statistics report that women constitute over 50 percent of the worldwide population living with HIV/AIDS, and the CDC reports that 23 percent of new AIDS diagnoses occur in women, indicating that women are the fastest growing group with HIV infection. Further, many of the early studies that investigated viral load levels and the use of viral load in the management of HIV included primarily men as research subjects rather than women. Thus, the question was raised: Does the current knowledge regarding viral load and its applications, validated primarily in men, apply to women as well?
Over the past decade, several studies have been performed to investigate that very question. Recently, investigators at the University of California-San Francisco, Johns Hopkins and the National Institutes of Health reviewed these studies and published a combined analysis of their findings. They reported that in seven of the nine cross-sectional (at a specific point in time) studies, women had viral loads that were approximately half that of men. Four other studies were performed in a longitudinal (following people with HIV over time) fashion and found perhaps even larger differences, reporting that women have viral loads that are 50-85 percent lower than men. These differences held even when accounting for age, race, medications, mode of transmission, CD4 count and time since seroconversion.
Because higher viral loads are associated with quicker progression to AIDS and poorer outcomes, this suggests that women may be able to suppress HIV infection better than men and would seem to be good news for women with HIV infection. Unfortunately, despite these differences in viral load, women progress to AIDS at the same rate as men. As an example, one study reported that the median initial viral load for men who developed AIDS was 77,822 copies per milliliter compared to 17,149 per milliliter for women.
The more alarming interpretation of these results, then, is that women progress to AIDS at much lower viral loads than men. This raises further questions: Should viral load be reduced to even lower levels in women before initial HAART therapy is deemed successful? Should smaller increases in viral load in women on a stable drug regimen be regarded as emerging resistance and trigger medication changes? If men and women progress to AIDS at similar rates, what, truly, is the role of viral load?
While the answers to these questions are lacking, speculation behind the reason for differences in viral load between men and women has already begun. Scientists note that this phenomenon may occur in other viral infections, such as in hepatitis C, where viral load levels are lower in women than in men. Other investigators note that HIV viral levels vary with the menstrual cycle in women and speculate that hormonal influences play a role. This is supported by studies that demonstrate that the cell-surface HIV receptors (CC5R), which facilitate HIV entry into cells, are present in lower numbers in women than in men. Further, in male-to-female transgender subjects who are receiving female hormones, CC5R receptors decrease to levels similar to biological women.
Thus, while the full meaning of lower viral load in women and its implications for the medical management of HIV infections are still unclear, this finding is likely to be a subject of ongoing research, discussion and continuing controversy. If nothing else, this serves as a reminder that clinical studies must include diverse populations and examination of sub-populations in their protocols -- because the small differences that gives us our individual characteristics, cultures and personalities may have larger implications for the successful treatment of HIV infection.