Balance of evidence continues to show: undetectable viral load in blood does not equal zero infection risk

Michael Carter
Published: 18 January 2008

The level of HIV viral load in blood and semen is related, but studies looking at the correlation between HIV in blood and semen have yielded a wide variety of results, according to a review article analysing the results of 19 studies examining this issue published in the January 2008 edition of Sexually Transmitted Diseases. The review article’s authors found that the association between viral load in blood and semen was affected by a number of factors, with successful antiretroviral therapy strengthening the association and sexually transmitted infections weakening it.

Prevention messages should stress the importance of condoms and other risk reduction strategies, regardless of whether a patient is taking effective anti-HIV therapy, recommend the investigators, as HIV transmission is possible even if a patient has an undetectable viral load in their semen.

HIV is mainly transmitted by unprotected anal and vaginal sex. Since the earliest days of the HIV epidemic it has been known that the virus is present in both blood and genital fluids. Infection with HIV is dependent upon the exposure of susceptible cells to an infectious quantity of HIV and it is known that concentrations of HIV in genital fluids, such as semen can vary.

HIV viral load levels in blood and semen are related but are not equal. It is not possible to determine how infectious an HIV-positive individual is on the basis of their blood viral load unless the extent of the association between viral load in blood and semen is determined.

Understanding the relationship between viral load in blood and semen is essential for estimating the potential benefit for antiretroviral therapy to reduce the risk of HIV transmission.

Investigators from the University of Connecticut therefore reviewed studied that measured viral load in blood and semen at the same time. The investigators examined the correlation between viral load in the two and the factors affecting this.

A PubMed search in January 2007 together with a search of abstracts of research presented to the Conference on Retroviruses and Opportunistic Infections (CROI) and the conferences of the International AIDS Society yielded 19 eligible studies.

The investigators caution that most of these studies had a small sample size. Furthermore 17 had a cross-sectional design and only two were prospective.

Correlations between levels of HIV in blood and semen in the 19 studies ranged between 0.07 and 0.64.

But one study found an almost perfect (94%) concordance between viral load in blood and semen. The authors note that this was the most rigorously designed study, with all the men taking potent anti-HIV therapy and none having sexually transmitted infection.

A consistent finding of the study was that viral load was lower in semen than blood. In most of the studies, men who had undetectable virus in their semen also 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 in their blood.

Four factors were identified that could potentially influence the relationship between viral load in blood and semen: sexually transmitted infections; anti-HIV therapy and adherence; drug resistance; and the stage of HIV infection.

Infections such as gonorrhoea and chlamydia (which cause inflammation in the urethra) were found to significantly increase levels of HIV in semen. Some studies also suggested that a greater numbers of sex partners and higher rates of sexual intercourse also increased genital shedding of HIV.

Because sexually transmitted infections increase viral load in semen but not in blood, the correlation between viral load in the two is lowered. The investigators stress, “in fact, the studies with the lowest correlations between blood plasma viral load and semen viral load are those that are most likely to have included men with co-occurring sexually transmitted infections.”

Most of the studies showed that anti-HIV therapy suppressed viral load in semen. But there was also evidence that some anti-HIV drugs did not penetrate the blood and semen with equal efficiency. But in ideal conditions, when men were taking an effective antiretroviral regimen, were fully adherent to their therapy, and did not have a sexually transmitted infection, then there was a 95% certainty that below 4% of men with an undetectable viral load in their blood would have a detectable viral load in their semen. However, the investigators note, “these optimal conditions are rarely met outside of research settings.”

Poor adherence to anti-HIV therapy was associated with detectable HIV in semen in some studies, and another study showed that the men who missed the fewest treatment doses had the greatest degree of HIV suppression in semen over time.

Men who are treated with anti-HIV therapy can develop drug-resistant virus in their semen, and there is evidence of multi-drug resistant strains of HIV developing in the genital tract but not blood. The investigators note, “there is considerable alarm about the potential spread of multiple drug-resistant HIV from men with resistant HIV in their semen who contract a co-occurring sexually transmitted infection…when HIV is poorly controlled, the risk of transmitting treatment-resistant variants is particularly high.”

There were conflicting findings about the relationship between CD4 cell count and the level of viral load in semen, but no study found that the presence of symptoms of HIV disease influenced the association between viral load in blood and semen.

The investigators note that there is research evidence that some men (HIV-positive and uninfected) who believe an undetectable viral load means a lower risk of transmission are more likely to have unprotected sex. The investigators are concerned that this could lead to an increase in the number of men who have risky sex, offsetting the “protective benefits of reductions in semen infectivity.”

Furthermore, the investigators note that semen that has an undetectable viral load is still potentially infectious, and that cells in semen can contain HIV proviral DNA and can act “as vehicles for sexual transmission of HIV.”

They also note that the antiretroviral-treated men most likely to report unprotected sex are those most likely to have poor adherence to antiretroviral therapy. Treatment non-adherence increases viral load and unprotected sex involves a risk of sexually transmitted infections. The investigators are concerned that unprotected sex occurring in the context of poor adherence and sexually transmitted infections could result in the transmission of drug-resistant virus.

The investigators recommend that “HIV prevention messages targeted to both infected and uninfected persons should communicate the importance of condoms and other risk reduction strategies regardless of HIV treatment status and at all stages of HIV disease. Perhaps most crucially, HIV prevention for people living with HIV…must include regular monitoring and aggressive treatment of co-occurring sexually transmitted infections.”


Kalichman SC et al. Human immunodeficiency virus load in blood plasma and semen: review and implications of empirical findings. Sexually Transmitted Diseases 35: 55 – 60, 2008.

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