People who contract HIV once can contract it again, often through the same risk behaviors that led to the initial infection. A long-standing question has been whether getting infected with a second strain of HIV leads to more rapid HIV disease progression than infection with a single strain.

To this point, a 24-year-old man who has sex with men recently asked me, "Doc, I already rang the bell, why do I care if I get HIV again?"

The first hints of an answer to this question arrived nearly 20 years ago. In 1997, researchers reported rapidly progressive immunodeficiency in a patient infected with two distinct strains of HIV. Since the patient mounted only weak immune responses to both viruses, the investigators could not determine if infection with two strains of HIV -- which they termed "dual infection" -- was the cause of the man's rapid disease progression or if other factors, such as his weak immune responses, were more to blame.

More evidence accrued in 2002 when investigators at the Massachusetts General Hospital showed that a patient with previously well-controlled HIV infection and robust T-cell responses against the virus later developed accelerated disease progression after infection with a new strain of HIV. They termed infection with a new strain of HIV "superinfection," and many in the HIV community worried that these findings cast doubt on the possibility of durable immune protection from diverse HIV viruses.

Neither report in individual patients could address whether dual infection or superinfection were associated with poorer clinical outcomes compared to infection with a single virus. In 2004, a study among five patients with dual infection -- including one with superinfection -- suggested that the average time to disease progression was under four years, i.e., faster than we expect routinely.

These data have helped guide clinical practice. Many clinicians urge patients with HIV to practice safer sex in part to avoid superinfection either because it could result in worsening HIV disease progression or because it may lead to the acquisition of a more resistant strain.

Now a new paper evaluates clinical outcomes in 21 female sex workers in Mombasa, Kenya, the largest cohort of people with proven HIV superinfection. To determine if HIV disease progression was impacted by superinfection, the investigators led by Julie Overbaugh in Seattle compared pre- and post-superinfection HIV viral loads and CD4 counts. They found a nearly significant increase in HIV viral load after superinfection (+0.21 log10, P = .09), but no difference in pre- and post-superinfection CD4 counts. In separate analyses, compared to women only infected with a single virus, women with superinfection showed slightly more rapid increases in HIV viral load over time (0.009 log10 HIV copies/mL/month faster viral load increase [P = .0008]) and a trend toward faster CD4-count decline. Despite these associations of superinfection with poorer virological control and potentially more rapid immunological deterioration, women with superinfection had the same disease progression-free survival as women infected with only one strain of HIV.

This is by far the largest study of people with HIV superinfection, and is thus an important contribution. Yet, it is still a small study that might not have been powered to detect subtle increases in the rate of HIV disease progression after superinfection. However, the authors' contention that HIV superinfection caused "no large difference in clinical outcome" is undeniably true.

When we counsel patients about HIV superinfection, we should not warn them that superinfection will quicken disease progression -- the best data available suggest this may not be true. However, patients do need to know that superinfection with a strain of HIV that is resistant to their current antiretroviral regimen could undermine treatment success. Most importantly, patients need to know that safer sex can help prevent other sexually transmitted infections, such as drug-resistant gonorrhea.

This is what I told my 24-year-old patient with HIV. He had indeed "rang the bell" already, but safer sex is still a good idea because there are many more bells out there that he does not want to ring.

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