Australian Herpes Management Forum

HSV in HIV-Infected Individuals

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Compiled by the Board of the Australian Herpes Management Forum

Introduction

There are a number of ways in which HSV and HIV interact, first to enhance transmission of both viruses, and second in a number of clinical manifestations. In addition, both viruses are transmitted sexually and are found in high prevalence among specific risk groups of individuals.

• HSV infection increases the risk of acquiring HIV
• HSV-2 increases the HIV viral load
• HSV-2 increases the genital shedding of HIV
• HIV increases the frequency of recurrences of symptomatic HSV

HIV Transmission and Herpes simplex viruses

Genital Herpes Ulcers

It has been known for many years from epidemiological and natural history studies, that the ulcerative STIs lead to an increased risk of HIV transmission¹. Ulcerative STIs lead to disruption of the mucosal or skin surface—the portal of entry for HIV and to an up-regulation of pro-inflammatory and immuno-regulatory cytokines. In addition, ulcers may bleed thus increasing the risk of HIV transmission. Many studies have shown that genital ulcer disease leads to a 2-5-fold increase in the risk of HIV acquisition.

HSV-2 is the most common cause of genital ulceration worldwide, in both the developed² and the developing world³. A cross-sectional study from South Africa of 558 men with genital ulcers showed that HSV-2 was the most common agent identified in ulcer specimens (35.9%), and was detected in a significantly higher proportion of ulcer specimens from HIV-infected patients than in specimens from HIV-uninfected patients (47.4% versus 28.2%, p0.001). A recent study looking at the changes in genital ulcer disease in Botswana from 1993 to 2002 found that the observed proportion of cases of genital ulcer disease due to chancroid decreased from 25% in 1993 to 1% in 2002, whereas the proportion of ulcers due to herpes simplex virus increased from 23% in 1993 to 58% in 2002⁴. Of all the ulcerative STIs, infection due to HSV-2 appears to carry the greatest increased risk of both HIV susceptibility and HIV transmission.

Positive HSV-2 Serology and HIV Transmission

A review of the two ‘overlapping epidemics’ by Corey et al⁵ discusses the more than 30 epidemiological studies that point to the 2- to 4-fold increased risk of HIV-1 acquisition associated with prevalent HSV-2. A recent meta-analysis of 31 studies, involving over 25,000 people, indicates that HSV-2 seropositivity itself, regardless of associated clinical disease, is a risk factor in the acquisition and transmission of HIV infection. The authors found that for 9 cohort and nested case-control studies that documented HSV-2 infection before HIV acquisition, the risk estimate was 2.1 (95% confidence interval, 1.4-3.2). Thus, the attributable risk percentage of HIV to HSV-2 was 52%, and the population attributable risk percentage was 19% in populations with an HSV-2 prevalence of 22%. This increased to 47% in populations with 80% HSV-2 prevalence. The population attributable risk is an epidemiological term referring to the proportion of cases of a condition within a population that can be attributed to another cause⁶.

For 22 case-control and cross-sectional studies, the risk estimate was 3.9 (95% confidence interval, 3.1-5.1)⁷. The largest study, which was included in this meta-analysis, showed that HSV-2 infection is a risk factor for the acquisition of HIV among homosexually active men⁸. This nested, case-control study of 116 seroconverters and 342 controls (men who did not seroconvert to HIV) at two sites in the USA showed an odds ratio for HIV acquisition of 1.8 (95% confidence interval, 1.1-2.9) for those men who were HSV-2 seropositive. The study controlled for number of sexual partners, among other variables. The risk of HIV acquisition was highest for those with recent acquisition of HSV-2.

A cross-sectional study published in 2004 which looked at 221 couples (in which at least one member was HIV-positive) in 4 African cities found the only significant risk factor for HIV concordancy was HSV-2 status (24). After adjusting for age and city of residence the odds ratio for HIV concordancy compared to couples with neither spouse HSV-2 positive was 3.4 (95% confidence interval, 0.62-18.4) for couples with one partner HSV-2 positive and 8.6 (95% confidence interval, 1.6-45.0) for couples with both partners HSV-2 positive.

Antiherpes medications reduce HIV viral load in blood and genital fluids

A study published in 2002 showed that the HSV shedding rate was strongly correlated with plasma HIV-1 viral load⁹. Moreover, suppression of HSV with aciclovir was associated with a measurable decrease in plasma HIV-1 RNA levels—the median reduction in viral RNA load was > 5000 copies/ml.

A more recent study using 500mg valaciclovir twice daily showed reduced HIV-1 plasma levels by more than 50% in men infected with both viruses, as well as reducing HIV viral loads in rectal fluids¹⁰.

Should antiherpes medication be prescribed to reduce HIV transmission?

Given the strong epidemiological evidence, coupled with the biological plausibility, large randomised trials have been undertaken to determine whether providing acyclovir to those with HIV. The results of 2 of those are currently available, and neither study showed that giving aciclovir to people with HSV-2 who are at high risk for HIV infection actually reduced their risk of acquisition.

A large, randomised control trial enrolled 1,358 HIV-negative but HSV-2 positive women at 3 sites in Africa and 1,814 men who have sex with men—also HIV-negative and HSV-2 positive—at 3 sites in the U.S. and 2 in Peru. Participants were randomised to receive either 400mg aciclovir twice daily or placebo and were seen monthly to be given the drug, for measurement of adherence (by pill count and self-report), and for risk reduction and adherence counselling. The researchers found the incidence of HIV was 3.9 per 100 person-years in the aciclovir group compared with 3.3 in the placebo group. The hazard ratio was 1.16, with a 95% confidence interval from 0.83 to 1.62. The incidence of genital ulcers was reduced by 47% in the aciclovir group, compared with the placebo group. Adherence to the study drug or placebo was 94% in both groups¹¹.

Other studies are currently under way to determine whether antiherpes medication can reduce the infectiousness of HIV in those with HSV-2.

Recommendation 1: Giving aciclovir to people with HSV-2 does not reduce their risk of contracting HIV infection, and cannot be recommended.

Recommendation 2: Giving aciclovir to people with co-infected with HIV and HSV-2 does not reduce their risk of HIV transmission, and cannot be recommended.

HSV-1 and HIV transmission

It has been very difficult to show any effect of HSV-1 on HIV transmission. This is possibly due to the very high rates of HSV-1 in at-risk populations, with most disease likely to occur in the orofacial region, rather than the genitalia, as for HSV-2.

Recently, researchers with the HIM (Health in Men) gay male cohort from Sydney (Fengyi et al. ISSTDR 2007 abstract O-001) observed a significant association between HSV-1 and HIV infection, but not between HSV-2 and HIV. They had previously found that the incidence rate for HSV-1 in their cohort was much higher than for HSV-2 -12 5.58 versus 1.45 per 100 person-years, respectively.

Recommendation: More studies are needed into the effect of HSV-1 on HIV transmission.

Treatment of HIV-positive individuals with antiherpes medications

In people with low CD4 counts, particularly below 100 x 10⁶/l, herpes lesions can be persistent, rather than self-limiting. HIV immunosuppression also increases the likelihood that the response to antiherpes medication will be poorer.

A chronic herpes simplex ulcer of more than one month’s duration (or HSV bronchitis, pneumonitis or oesophagitis) remains an AIDS-defining illness. These infections are now mercifully rare in the age of potent antiretroviral therapy, though they still occur occasionally in developed countries, and are not uncommon in populations without access to such therapies.

Prior to the era of potent antiretroviral medications, 2 studies showed a survival benefit in those individuals with HIV who were treated with aciclovir¹³. One other study showed no such benefit. A subsequent meta-analysis of 8 randomised trials showed a survival benefit for treatment with aciclovir 3200–4800 mg per day¹⁴.

Suligoi et al found that aciclovir did not significantly prolong survival (n=126 HIV-positive individuals). Multivariate analysis showed treatment gave a 37% protective effect against progression to AIDS, but, when antiretroviral therapy was included in the analysis, this protective effect decreased to 9%¹⁵.

Aciclovir-unresponsive herpes simplex disease is uncommon, and a USA study showed 12 of 226 HSV-2 isolates from HIV-positive individuals were resistant to aciclovir¹⁶. No HSV-1 isolates were found to be aciclovir-resistant, and all 15 patients with aciclovir-resistant isolates had reported repeated lesions and aciclovir use in the previous year.

If clinical disease does not respond to aciclovir, then a newer agent such as valaciclovir or famciclovir should be tried. The higher serum levels of active agents that these medications provide are frequently effective. Foscarnet and cidofovir are other agents that may be effective in aciclovir-unresponsive disease.

Studies looking at the outcomes of treatment with antiherpes medications have been carried out in HIV-positive participants. Shacker et al (2003) conducted a study in 48 HIV-infected people, with a median CD4 count of 384 x 10⁶/l. Famciclovir 500mg twice daily was compared with placebo, and viral shedding was decreased significantly, as were days with HSV lesions. Conant et al (2002) conducted a larger study of 1062 subjects and compared valaciclovir 500mg twice daily to valaciclovir 1g daily, to aciclovir 34000mg twice daily for 48 weeks. Valaciclovir performed better than aciclovir with regards to time to first recurrence of clinical HSV.

Romanowski et al (2000) looked at 293 subjects and compared famciclovir 500mg daily to aciclovir 400mg 5 times daily. 16.7% of FCV vs 13.3% of ACV recipients developed new lesions. Shacker et al (2002) compared valaciclovir 500mg twice daily to placebo for 6 months. 80% of valaciclovir, compared with 38% of placebo recipients were recurrence free, giving a relative risk of 2.1.

There are no significant interactions between antiherpes agents and the antiretroviral medications.

Recommendations for treating people with IV with antiherpes agents: The recommended agents for treating, or suppressing, HSV recurrences in those with HIV infection is ether valaciclovir 500mg twice daily, or famciclovir at the same dose.

Should all people with HIV infection be routinely tested for HSV?

Guidelines from the IHMF in 2004 recommend that HIV-positive persons should be serologically tested for HSV-2 infection and counselled about clinical and public health implications. The reasons for this recommendation include:

• People with HIV are at higher risk for HSV-2 infections
• Most HSV infections are unrecognised, even in people with concomitant HIV infection
• The sensitivity and specificity of commercially-available type-specific serological tests are very good in high prevalence populations
• The tests are cheap (the fee for a single serological assay is $15.90 on the Medicare Benefits Scheme) and widely available
• The psychological effect of a positive HSV-2 diagnosis on those with HIV is minimal¹⁷.

The Sydney, NSW, based STIGMA (Sexually Transmissible Infections in Gay Men Action Group) guidelines recommend that clinicians “Consider herpes simplex virus (HSV) type specific serology”¹⁸

Recommendation for testing of individuals with HIV infection: Testing for HSV with type-specific serology should be routinely offered to people with HIV-AIDS.

Maternal HSV-2 and Perinatal HIV-1 Transmission

Perinatal transmission of HIV is a major public health problem particularly in women in sub-Saharan Africa and is associated with low CD4 counts and high viral loads. Two case-control studies looking at the association between HSV-2 and perinatal HIV-1 transmission have recently been published. The first was a relatively small study from the USA involving 26 HIV positive woman and 52 controls and this study showed no association between the HSV-2 prevalence and HIV transmission¹⁹.

However, a much larger study from Zimbabwe involving 509 cases and 1018 controls showed that 28.4% (95% confidence intervals 7.3-44.7%) of perinatal HIV-1 transmissions were potentially attributable to HSV-2²⁰. In both studies HSV-2 prevalence was extremely high in patients and controls (over 80%) and the reason for the different findings between these two studies may have been due to lack of power in the first study due to the small sample size. Further studies are underway to determine whether antiviral treatment of HSV-2 in late pregnancy will reduce HIV-1 transmission. Suppressive aciclovir has been shown to reduce the cervicovaginal shedding of HIV-1 in women who are HSV-2 seropositive²⁰, but there are as yet no data to show that this leads to a decrease in perinatal transmission of HIV.

Recommendation: Pregnant women who are co-infected with HSV-2 and HIV should be managed in accordance with standard practice in regard to antiretroviral therapy and prevention of mother to child transmission. Women with clinical recurrences of genital herpes may require either episodic or suppressive therapy.

References

1. O’Farrell N. Targeted interventions required against genital ulcers in African countries worst affected by HIV infection. Bull World Health Organ 2001;79:569-577.
2. Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997;337:1105-1111.
3. Chen CY, Ballard, RC, Beck-Sague CM, Dangor Y, Radebe F et al. Human immunodeficiency virus infection and genital ulcer disease in South Africa: the herpetic connection. Sex Transm Dis 2000;27:21-29.
4. Paz-Bailey G, Rahman M, Chen C, Ballard R, Moffat HJ, et al. Changes in the etiology of sexually transmitted diseases in Botswana between 1993 and 2002: implications for the clinical management of genital ulcer disease. Clin Infect Dis 2005;41(9):1304-12.
5. Corey L, Wald A, Celum CL, Quinn TC. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004;35(5):435-45.
6.  Uter W, Pfahlberg A. The application of methods to quantify attributable risk in medical practice. Stat Methods Med Res 2001;10(3):231-7.
7.  Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: a meta-analysis. J Infect Dis 2002;185:45-52.
8.  Renzi C, Douglas JM, Foster M, Critchlow CW, Ashley-Morrow R, et al. Herpes simplex type 2 infection as a risk factor for human immunodeficiency acquisition in men who have sex with men. J Infect Dis 2003;187:19-25.
9.  Schacker et al, J Infect Dis 2002;186:1718-1725
10.  Zuckerman RA, et al "Herpes Simplex Virus (HSV) Suppression with Valacyclovir Reduces Rectal and Blood Plasma HIV-1 Levels in HIV-1/HSV-2-Seropositive Men: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial" JID 2007; 196: 1500-08.
11.  Celum C, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: A randomised, double-blind, placebo-controlled trial. Lancet 2008; 371: 2109-19.
12.  Jin F et al. Transmission of herpes simplex virus types 1 and 2 in a prospective cohort of HIV-negative gay men: the health in men study. JID 2006; 194(5):561-70.
13. Cooper et al, AIDS, 1993; Youle et al, AIDS, 1994
14.  Stein et al, Ann Intern Med, 1994
15.  Ioannidis et al, J Infect Dis, 1998
16.  Suligoi et al (Antivir Ther 2002)
17.  Reyes et al, Arch Intern Med 2003;163:76-82).
18.  Sex Transm Infect (Meyer JL et al. 2005;81:309-315)  http://www.ashm.org.au/uploads/STIGMA_STI_Testing_Guidelines_for_MSM.pdf Accessed 17 Sep 2008
19.  Chen KT, Tuomala RE, Chu C, Huang ML, Watts DH, Zorrilla CD, et al. No association between antepartum serologic and genital tract evidence of herpes simplex virus-2 coinfection and perinatal HIV-1 transmission. Am J Obstet Gynecol. 2008;198(4):399 e1-5.
20.  Cowan FM, Humphrey JH, Ntozini R, Mutasa K, Morrow R, Iliff P. Maternal Herpes simplex virus type 2 infection, syphilis and risk of intra-partum transmission of HIV-1: results of a case control study. AIDS. 2008;22(2):193-201.

 Disclaimer

The AHMF have made considerable efforts to ensure the information upon which this guideline is based reproduces the evidence as accurately as possible. Users of this guideline are strongly recommended to confirm that the information contained within it, especially drug indications, is correct by way of independent sources, as this guideline does not indicate an exclusive course of action or serve as a standard of medical care. The AHMF accepts no responsibility for any inaccuracies, information perceived as misleading, or success of any treatment regime detailed in this guideline.