Herpes Simplex Virus-2 in HIV-Coinfected Patients: Prevention, Diagnosis, Management (Archived Web Conference)

Martin Irvine: I'm Dr. Martin Irvine, Executive Editor of Medscape, and I would like to welcome you to our live Web conference: "Herpes Simplex Virus-2 in HIV-Coinfected Patients: Prevention, Diagnosis, and Management." This is a continuing education activity made possible by an independent educational grant from GlaxoSmithKline.

Before we begin, let me take a few moments to go over the format of tonight's program. We will begin with a presentation from Dr. Connie Celum, who will discuss the epidemiology and interactions between HSV-2 [herpes simplex virus-2] and HIV. This will be followed by a presentation from Dr. Anna Wald, who will discuss the presentation, diagnosis, and management of HSV-2 in HIV-infected patients.

Each presentation will last around 15-20 minutes, and at some point during each presentation, there will be a simple polling question for you, the audience, to answer. At the completion of each presentation, there will be a brief question and answer session.

I would like to introduce our first presenter, Dr. Connie Celum, Professor of Medicine at the University of Washington in Seattle.

Connie Celum: Good evening. In brief, what I will be covering are the data that demonstrate the epidemiologic and biological evidence for interactions between HSV-2 and HIV, then the public health implications, and briefly describe some intervention trials that are ongoing to try to address whether we can interrupt these interactions.

Slide 4 highlights several key issues about HSV-2 that are important to be aware of.

First, it's highly prevalent. In studies done in the United States, approximately 1 out of 5 sexually active adults is HSV-2-seropositive. In studies in Latin America and Peru, specifically, 60% of HIV-uninfected men who have sex with men are HSV-2-seropositive. The rate is even higher among HIV-infected women in parts of sub-Saharan Africa, South Africa, and Zimbabwe, where the HSV-2 prevalence is 70%. Over 80% of HIV-infected men and women globally are HSV-2-infected. If you look across studies, the data suggest that HSV-2 prevalence increases with age and that, consistently, women have higher prevalence than men.

One of the challenges is that most people do not recognize their clinical manifestations. They have subclinical recurrences, so that as many as 80% to 90% of individuals who are HSV-2-seropositive at the time that they are tested don't recognize genital ulcer disease. However, after counseling, most people can learn to recognize genital herpes.

As Dr. Wald's presentation will summarize as well, HSV-2 clinical manifestations are very diverse and often subtle. However, even those persons who are asymptomatic do shed herpes virus, as measured by polymerase chain reaction (PCR); thus, they are infectious.

Slide 5 summarizes the main interactions between HSV-2 and HIV.

First, a number of studies now suggest that HSV-2 infection increases the risk of HIV acquisition on average of 2-fold, based on a meta-analysis that my colleague, Dr. Anna Wald, conducted several years ago.

Data from Rakai, Uganda, in HIV-discordant couples suggests that, on a per-contact basis, HSV-2 increases the risk of HIV acquisition 5-fold. These data suggest that genital herpes increases the risk and basically one's susceptibility to HIV if you're HSV-2-infected.

There are also data, primarily from Rakai, Uganda, that suggest HSV-2 can increase the risk of HIV transmission (ie, increase one's HIV infectiousness if you're coinfected with HSV-2). These data also suggest a 5-fold increased risk on a per-contact basis among HIV-infected individuals who have genital herpes lesions.

The third interaction is that HIV changes the natural history of HSV-2. There are more frequent, both clinical and subclinical, reactivations, and HSV-2 reactivation is increased among those who have lower CD4+ cell counts and higher plasma viral load.

During the HSV-2 reactivation, HIV levels are increased both in secretions obtained from genital herpes lesions as well as from genital secretions in plasma.

Slide 6 summarizes the meta-analysis that I mentioned earlier that my colleague, Dr. Anna Wald, conducted; this was published in 2002.

If you look at the best studies, namely, those in which you could demonstrate the timing of HSV-2 and HIV infection -- and at the time that this was published, there were 9 such studies -- there's an average increased risk of HIV acquisition of 2-fold.

There were a larger number of studies where you couldn't time the HSV-2 and HIV infections, primarily because they were cross-sectional studies. Data from those studies suggested that there was even a higher risk, but again, that's limited because you didn't know which came first, HIV or HSV-2.

Given these issues, most people would choose to take the more conservative figure of a 2-fold increased risk of HIV acquisition, when you control for exposure and behavioral factors.

We take that figure of a 2-fold increased risk and enter it into an equation that epidemiologists use, called the population attributable risk, which tries to estimate what proportion of new HIV infections might be due to the HSV-2 factor.

If you look at it based on the HSV-2 prevalence data that I showed in slide 4, among the general population in the United States, one would predict that about 20% of new HIV infections would be due to HSV-2.

Whereas it's higher (35%) in populations, such as US or Latin American men who have sex, and reaches almost 50% in populations with the highest HSV-2 prevalence, such as those in some regions of sub-Saharan Africa.

What this indicates is that if we were able to eliminate the cofactor of HSV-2 infection, we might be able to have a substantial impact on reducing the numbers of new HIV infections.

In slide 8, there are data summarized from a cohort study in India that were published a couple of years ago, in which they looked at HIV-acquisition risk among cohort of about 2,500 individuals. This study showed an important new finding: The risk was really the highest, about 3.5-fold higher risk of HIV acquisition, among those individuals who acquired HSV-2 within the prior 6 months. That's shown on the furthest right-hand bar, where individuals were at a 3.6-fold higher risk of HIV acquisition, compared to those individuals who were HSV-2-negative. There was also an intermediate risk among those who came into the study HSV-2-infected or acquired it 6 months or before.

To summarize, these data suggested that the risk might be highest among those individuals who recently acquired HSV-2 infections.

The epidemiologic data in slide 9 suggest that HSV-2 infection increases the risk of HIV acquisition 2-fold, and this was observed regardless of whether individuals previously had reported or recognized genital herpes symptoms.

The hypothesis is that HSV-2 increases HIV susceptibility by providing a portal of entry, even a microscopic one, at which one can identify activated CD4 cells that are the target for HIV infection.

However, there's always a concern in these kinds of studies that you can never fully address the behavioral risk factors and remove the concerns about unmeasured behavioral confounding. These are all based on observational studies.

Another hypothesis is that we know that herpes reactivates more frequently and the lesions last longer in the first year to 2 after HSV-2 acquisition, so this cofactor might be particularly important recently in the period after individuals acquire HSV-2.