Important note: Information in this article was accurate in March 2010. The state of the art may have changed since the publication date. 
Part of the reason that HAART is so effective is that it can greatly suppress the production of HIV in the blood. To assess HIV production (replication) in blood and other fluids, viral load assays are used. Back in the mid-1990s, the lower limit of quantification of viral load assays was 10,000 copies/ml. As this technology improved, viral load tests became available with a lower limit of quantification between 400 and 500 copies/ml, depending on the assay used. More recently, newer assays have a lower limit of quantification between 40 and 50 copies/ml. Viral loads below the lower limit of quantification are referred to as undetectable.
Some enthusiastic researchers, buoyed by the stunning clinical effects of HAART in 1996, predicted that prolonged undetectable viral load would result in HIV being cured after several years. Unfortunately, this has not turned out to be the case. We now know that an undetectable viral load, while a major clinical achievement, does not mean that HIV infection will gradually disappear or be cured. HIV still lurks in many tissues and within a range of cells found deep within the body, such as in the bone marrow.
In high-income countries today, the lower limit of quantification for routine viral load assays ranges between 40 and 50 copies/ml. Values below these levels cannot be accurately assessed by routine viral load assays. However, ultra-sensitive viral load tests that can accurately assess much lower viral loads have been developed for research purposes and some of them are likely to become available in the next several years for everyday use by physicians in North America and Western Europe. For routine clinical use, such assays will likely have a lower limit of quantification of 20 copies/ml.
As part of a clinical trial, researchers in Italy have been testing an ultra-sensitive viral load assay. Their assay has a lower limit of quantification of 2.5 copies; that is, it can accurately count viral loads as low as 2.5 copies/ml. The researchers focused their analysis on 154 people who had been taking HAART for about three years. During this time all participants had viral loads in the blood that were less than 50 copies/ml according to conventional viral load assays (i.e. “undetectable” according to the routine viral load test).
Using their ultra-sensitive assay, the Italian researchers found that nearly 60% of these participants had a viral load that could be detected--ranging from three to 46 copies/ml. This study and others have found that viral load that is undetectable using routine assays can be detected using ultra-sensitive assays. This suggests that HIV is being produced, albeit at low levels, despite effective HAART.
The results of these ultra-sensitive viral load assays emphasize that the concept of an “undetectable” HIV viral load is about the limits of a test and should not be misinterpreted to mean that there is no HIV in the blood (or in other tissues that are assessed for viral load).
Furthermore, it is important to note that viral load is dynamic; it can go up and down. Among HIV-positive people who adhere to their drug regimens, viral load levels in the blood can temporarily increase, usually between 41 and 200 copies/ml, without an apparent reason. These temporary increases are called blips. Viral loads can also increase from time to time because of infections, vaccinations, allergic reactions--circumstances that all stimulate the immune system and the HIV that lurks within it. Viral loads can also fluctuate in other parts of the body, such as the genital fluids, despite the use of HAART. Therefore, an “undetectable” viral load result in the blood does not always reflect what is going on the body.
Taking all of this information into account, it is likely that the risk of HIV transmission is dynamic--it can go up or down depending on circumstances, only some of which may be known.
Several research teams have found detectable HIV in semen samples of HAART-using men who have a viral load in the blood that is less than 50 or 40 copies/ml. We now briefly report on these research findings and their implications for HIV transmission.
Toronto-Intermittent HIV in semen despite HAART
A research team at the University of Toronto decided to monitor blood and semen samples from 25 HIV-positive men over a period of six months.
At the start of the study, the men were free from common sexually transmitted infections (STIs) such as Chlamydia, gonorrhea and syphilis. During the study they were repeatedly screened for STIs.
About two-thirds of the men received HAART consisting of efavirenz (Sustiva and in Atripla)-based regimens. The remaining men had regimens based on ritonavir-boosted atazanavir (Reyataz) or lopinavir-ritonavir (Kaletra).
By the 16th week of the study, all the men had viral loads in their blood that fell below the 50-copy mark. However, HIV was still detected in 50% of the men’s semen samples on more than one occasion. In four of these men, HIV levels in the semen were considered high--more than 5,000 copies/ml, according to the researchers.
There was no apparent relationship between specific anti-HIV drugs used and the detection of HIV in the semen.
The study team did find that men who had detectable HIV in their semen tended to have had higher viral loads in their blood prior to starting HAART (26,000 copies) compared to other men in the study (3,000 copies).
For purposes of comparison, the researchers assessed HIV levels in the blood and semen of 13 other HIV-positive men whose viral load in the blood had been less than 50 copies/ml every three months for an average of seven years because of HAART. All the men were also free from STIs. Researchers detected HIV in semen samples in four of these 13 men (31%).
The work by this Toronto study team shows that HAART can dramatically reduce HIV levels in the blood and semen. However, the researchers stated that “many” of their study participants had detectable HIV in their semen despite being adherent to therapy, having a viral load in the blood that was “undetectable” and being free from STIs.
The research team also made this point: They checked only for HIV that was cell-free; that is, HIV that is not attached to a cell. However, other researchers have found that HIV that is attached to cells can persist in semen despite the use of HAART. Thus, the Toronto team may have underestimated the infectious potential of semen samples from HAART users.
In summary, despite effective HAART and undetectable viral loads in the blood, HIV can periodically be found in semen. Furthermore, the Toronto researchers state that in these cases, their findings “suggest that some individuals may remain sexually infectious.”
Ottawa--HIV in semen despite HAART
Researchers at The Ottawa Hospital Research Institute have also been studying the issue of HIV in semen. In their study, they took blood and semen samples on the same morning from 33 HIV-positive men. Prior to this experiment, all of the men had viral loads in their blood at less than 50 copies/ml for an average of four years and their average CD4+ count was 655 cells. All 33 men were free from common STIs.
Researchers found that despite undetectable viral loads in the blood, two of the 33 men (6%) had the following viral loads in their semen:
One of the men had consistently suppressed viral loads in his blood every three months for the past five years and his CD4+ count was 756 cells. The other man had his blood viral load consistently suppressed for the past two years and his CD4+ count was 880 cells.
Based on their findings, the Ottawa team recommended “considerable caution in concluding that patients on HAART with suppressed viraemia are sexually non-infectious.”
Toulouse--Semen analyses
Researchers in Toulouse, France, were also interested in assessing viral loads in blood and semen so they obtained samples from 37 men. They found that eight of the 37 men (22%) had detectable HIV in their semen. Five of the eight men had been taking HAART for more than six months and had a viral load in the blood less than 40 copies/ml. The Toulouse team stated that its findings “highlight the residual risk of HIV-1 transmission during unprotected intercourse” in people with undetectable viral loads.
Paris--Intermittent HIV in semen
Researchers at the Hôpital Pitié Salpêtrière in Paris, France, have been collecting and analyzing blood and semen samples using an assay with a lower limit of quantification of 40 copies/ml when used on blood samples and 200 copies/ml when used on semen samples.
The researchers found that in seven of 145 men (5%) HIV was detected in semen samples despite blood viral loads being less than 40 copies/ml. Furthermore, men in this study were regularly screened for STIs and were taking HAART.
In monitoring further samples from these men, six of the seven had discordant results between blood and semen viral loads. This latter finding, according to the researchers, confirms previous studies that HIV’s presence in the semen can be “intermittent.” The study team warns that in HIV-positive men on HAART who do not have STIs, HIV can still be present in the semen.
Some researchers have speculated that in men whose viral load in the blood is less than 50 copies/ml, HIV in the semen may somehow be defective; meaning, it may be incapable of causing infection. Yet scientists who study HIV in the body’s tissues and who have analysed semen samples have made a surprising finding: In men using HAART whose viral load in the blood was less than 50 copies/ml, HIV could be detected in the semen. Furthermore, this virus was what they called “replication-competent”--capable of causing infection.
Researchers in Australia were interested in further understanding the link between people’s knowledge or perception of their partner’s viral loads and their subsequent sexual behaviour. They interviewed 102 men who became HIV positive within the past eight weeks about the high-risk activity that was linked to their infection and about what the study team called their “source partner”--the man believed to have infected them.
Most of the men interviewed were gay or bisexual and the average age was 36 years. All had engaged in unprotected anal intercourse with their source partner. Here is what the men disclosed about their source partner:
Perhaps the most interesting results were obtained from 21 men who disclosed that they knew their partner’s viral load the last time they engaged in high-risk sex. Nine of these 21 men (43%) reported that their HIV-positive partner had an undetectable viral load. All nine of these men had unprotected anal intercourse and subsequently tested positive for HIV.
These reports of HIV transmission despite undetectable viral load in the blood should not be surprising.
We thank the many researchers, including experts in infectious diseases, internal medicine, biostatistics and other specialties across Canada, the European Union and the United States who contributed their time for helpful review, discussion and research assistance.
--Sean R. Hosein
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