Viral load in semen

A review article¹ analysing the results of 19 studies examining the correlation between HIV in blood and semen published or presented between 1996 and 2006 concluded that the level of HIV in blood and semen is usually correlated, but not always.

A consistent finding of the review was that viral load tended to be lower in semen than blood and that men who had undetectable virus in their semen almost always had an undetectable viral load in their blood. But two studies identified individuals who had levels of HIV in their semen that were equal to, or greater than, that in their blood.

Four factors were identified that could potentially influence the relationship between viral load in blood and semen: sexually transmitted infections; antiretroviral therapy and adherence; drug resistance; and the stage of HIV infection. Some studies also suggested that a greater number of sexual partners and higher rates of sexual intercourse also increased genital shedding of HIV.

Most of the studies showed that potent antiretroviral treatment suppressed viral load in semen. But there was also evidence that certain drugs did not penetrate the blood and semen with equal efficiency. Poor adherence to treatment was associated with detectable HIV in semen in some studies; another study found that the men who missed the fewest treatment doses had the greatest degree of HIV suppression in semen over time.

The one study² that found an almost perfect concordance between viral load in blood and semen was the most rigorously designed study, with all the men taking effective antiretroviral therapy (all had viral load in the blood below 400 copies/ml) and none having a sexually transmitted infection. It estimated, with 95% certainty, that fewer than 4% of men with a blood plasma viral load below 400 copies/ml will have detectable viral load in semen.

Studies published since this review confirm that, in most cases, men with an undetectable viral load in the blood also have an undetectable viral load in semen, but that there are always exceptions. However, the threshold level of seminal viral load that corresponds to a significant transmission risk remains unknown.

A 1999 study³ looked at 94 gay men, 58 of them (61%) on HIV treatment, though twelve were on dual therapy. Six men (10%) on HIV treatment had detectable seminal viral loads (over 800 copies/ml). Although all of these had detectable blood plasma viral loads too, three of the four had blood plasma viral loads under 1000 copies/ml, while two of them had a seminal viral load over 10,000 copies/ml.

The same research team, in a study published in 2003,⁴ found that in seven out of every eight men not on treatment, their seminal viral load was one-tenth of their blood plasma viral load: the average blood viral load in this group was 110,000 copies/ml and seminal viral load 9200. However, one in eight men (9 out of 72 in the study) showed the reverse pattern and were dubbed ‘seminal super shedders’. In this group, the average blood plasma viral load was 64,000 copies/ml and the seminal viral load seven times higher at 460,000.

Ten years later, an assisted-conception study in Paris⁵ was presented at the 2009 CROI (Conference on Retroviruses and Opportunistic Infections). It found that, of 145 HIV-positive men enrolled in an assisted-conception study in France who had a blood plasma viral load under 40 copies/ml, seven men (5%) had detectable virus in their semen (over 200 copies/ml) despite having an undetectable viral load in their blood (defined here as below 40 copies/ml); seminal HIV RNA levels ranged from 255 to 1230 copies/ml.

Most of the detectable seminal viral load occurred as 'blips' – six of the seven men had previously had undetectable viral loads in both blood and semen on at least one other occasion. The men were on a variety of antiretroviral regimens, and the antiretroviral drugs present in the blood were consistently detectable in semen as well. The investigators note that all of these men had been taking antiretroviral therapy for at least six months and none had a documented sexually transmitted infection. 

A Canadian study⁶ also presented at CROI 2009 described a prospective cohort of 25 men initiating antiretroviral treatment. It found that seminal viral load was still detectable in some participants 24 weeks after the start of treatment, although all subjects had previously achieved an undetectable (<50 copies/ml) blood plasma viral load by 16 weeks.

HIV RNA was detectable in 19/116 (14%) of the samples taken after blood plasma viral load became undetectable. Cell-free virus isolated from the semen of the ‘highest shedder’ was found to be infectious in an in vitro test. (No other patients' samples were analysed.)

Patterns of viral shedding varied: one man had persistent, sustained seminal HIV without ever reaching undetectability, but most had single ‘blips’ among otherwise undetectable measurements. Nine of the twelve detectable measurements (75%) occurred after seminal viral load had initially become undetectable.

A second part of the study examined single samples from 13 men in whom HIV had been suppressed on treatment for a median of 82 months and found detectable virus in the seminal fluid of four (31%). The only predictor of detectable seminal viral load was a higher pre-treatment viral load; there was no association with type of ARV regimen, nor with drug concentrations in seminal fluid.

This study used a branched-DNA viral load assay (b-DNA), which is more sensitive than the more often used PCR viral load assays, possibly explaining why this study found somewhat higher values than other studies of HIV in semen have found (including the Paris study).

A French case report⁷ also suggested that seminal viral load may fall more slowly than viral load in blood. A patient had an undetectable viral load in blood (under 400 copies/ml) by his fourth month of therapy, but his seminal viral load was still detectable in the sixth month, despite a change in his regimen from AZT/3TC/fosamprenavir/r to tenofovir/FTC/lopinavir/r. His seminal viral load finally fell below 400 at the eleventh month after starting therapy. The reasons for this are still mysterious but may be due to differential penetration of HIV drugs into the semen: lopinavir was the only drug detectable in his semen. 

HIV is present in semen both as cell-free virus, measurable as RNA in the seminal fluid itself, and as proviral DNA contained within lymphocytes (white blood cells) in the semen. Until recently, it was not known which of these was responsible for sexual transmission.

A study⁸ from the University of California, San Diego, which presented data on four cases of male-to-male sexual transmission, concluded that cell-free virus in semen – not proviral DNA in infected cells – was the means of transmission in all four cases. The source of the cell-free virus itself – seminal lymphocytes or the blood – is still unclear, however.

A third source may be the prostate. In another study,⁹ three of nine men with an undetectable HIV viral load in both their blood and semen had at least one semen sample each with detectable HIV after prostate massage – something likely to happen in anal sex.