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A correction has been published: N Engl J Med 2007;356(14):1487.
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HIV replication is compartmentalized in anatomic sites of the body, and the interactions between HIV type 1 (HIV-1) and microbes occupying these anatomic sites influence the amount and strain of HIV-1 in these regions. Interactions between the gut flora with HIV in gut lymphoid tissue and between sexually acquired pathogens and HIV-1 in the genital tract are perhaps the two areas of greatest importance in influencing the progression of disease and viral transmission. Localized infections of the genital tract with sexually acquired bacterial infections such as Neisseria gonorrhoeae and, to a lesser extent, Chlamydia trachomatis are associated with higher amounts of HIV in genital secretions; treatment of these infections with antimicrobial agents is associated with a lowering of the HIV load in these secretions.2 Thus, the identification and treatment of such infections have been important parts of the medical care of patients with HIV infection.
The clinical management of herpes simplex virus type 2 (HSV-2) in patients with HIV infection has lagged seriously behind the large body of medical literature on the importance of the interaction between these two pathogens.3 Persistent HSV-2 infection was one of the original opportunistic infections that resulted in the identification of HIV. Since the initial reports in 1988 studying men who have sex with men, many additional studies have shown the association between prevalent and incident HSV-2 infection and the risk of HIV acquisition.4,5 In this issue of the Journal, a study by Nagot et al.6 underlines the association of HSV-2 with significantly higher amounts of HIV-1 in plasma and in genital secretions in women with sexually acquired HIV-1. This finding has direct clinical implications, suggesting that HIV-1 replication can be reduced with antiviral therapy directed solely at HSV-2, since acyclovir has no direct antiviral activity against HIV.7
The conceptual importance of this observation is high. HSV-2 is acquired rapidly after the onset of coitus in sub-Saharan Africa. Among patients with HIV infection, HSV-2 infection is also present in 30 to 70% of those in Europe and 50 to 90% of those in Africa.3 As Nagot et al. show with sampling every two weeks, 50% of patients who are coinfected with HSV-2 and HIV-1 shed HSV-2 virus asymptomatically; with daily sampling, 75 to 95% of such patients shed HSV-2 virus in the genital tract, and the mean frequency of shedding is 40% of days. More than 85% of shedding episodes are subclinical, and highly active antiretroviral therapy (HAART) has little influence on either the frequency or titer level of mucosal HSV-2 shedding.8 Thus, most people worldwide with sexually acquired HIV have virologically active HSV-2 infection. HIV-1 is shed from genital ulcers caused by HSV-2; viral variants of HIV-1 that arise from these ulcers can appear and persist in plasma,9 and most important, these frequent subclinical episodes of HSV-2 reactivation are associated with both a higher frequency and a higher amount of HIV-1 in genital secretions.6 Both clinical and subclinical reactivations of HSV-2 are associated with the influx of activated CD4+ T cells into the genital mucosa and skin, and several HSV-2 proteins are capable of reactivating latent HIV infection. These interactions appear to account for the higher titers of HIV-1 in plasma in coinfected patients.
Multiple studies have shown that a persistent increase of 0.5 log10 copy per milliliter in the plasma HIV-1 level is associated with a clinically shortened time for progression to AIDS.10 The demonstration that daily anti–HSV-2 therapy can reduce the viral load by this amount is thus of direct importance for treatment. The study by Nagot et al. underlines the findings of a 1989 study showing that zidovudine plus acyclovir was associated with prolonged survival, as compared with zidovudine alone.11 The recent studies evaluating the effect of antiviral therapy for HSV-2 among patients with HIV-1 infection have used relatively short courses of anti–HSV-2 therapy (3 to 4 months). Although this duration of anti–HSV-2 therapy has been sufficient to demonstrate the importance of HSV-2 in influencing HIV replication, the results do not provide clinicians with definitive findings to quantitate the benefit and to guide clinical management. Will the HSV-2 suppression in patients with HIV-1 infection who have not undergone antiretroviral therapy delay the loss of CD4+ T cells and prolong the time until the initiation of antiretroviral therapy? Will prolonged suppression of HSV-2 among patients receiving antiretroviral therapy delay the emergence of resistant HIV strains and recurrent HIV viremia? Trials of a longer duration of therapy that includes measurement of these clinical end points of progression of HIV-1 disease are needed.
As described by Nagot et al., the reduction of 0.5 log10 copy per milliliter in plasma HIV levels with anti–HSV-2 therapy is large enough to provide a potential clinical benefit. However, it is less clear whether such a reduction in mucosal genital HIV with anti–HSV-2 therapy is consistent enough to influence the role of transmission of HIV-1 to sexual partners. At present, sexual transmission of HIV-1 has a stronger correlation with plasma HIV levels than with the mucosal viral load.12 This finding may be related to the variability in collection and the accuracy of measurement in mucosal sampling, as compared with plasma sampling. Since systemic anti–HSV-2 therapy lowers both types of virus, the real question is whether routine use of anti–HSV-2 therapy will provide benefit both to patients by reducing the progression of HIV-1 and to the community by reducing transmission to others.
The interconnections between HSV-2 and HIV-1 are well documented; the vast majority of patients with sexually acquired HIV — whether they are women or men or live in Europe, North America, Africa, or Asia — also have HSV-2 infection. The study by Nagot et al. highlights the potential benefit that screening and treating subclinical HSV-2 infection may offer to patients with HIV infection. Many questions about the interaction between these two organisms remain, and larger studies with defined clinical end points are needed to move the medical literature on this interaction into more effective clinical and population-based management. In the meantime, clinicians may want to incorporate more routine HSV-2 testing into the initial evaluation of HIV-seropositive patients.
Dr. Corey is director of the University of Washington Virology Division, which has received grant support from GlaxoSmithKline and Novartis, two companies that make antiviral drugs for the treatment of HSV-2. However, he receives no salary support from these studies. Dr. Corey reports serving as a paid expert in a legal dispute over a valacyclovir patent and receiving consulting fees from Antigenics, which is developing an HSV-2 vaccine. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Fred Hutchinson Cancer Research Center, Seattle.
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