IAS: Daily aciclovir doesn't reduce HIV risk in HSV-2-infected women - was poor adherence the reason?

HSV-2 and HIV – a well-established link

The association between infection with HSV-2 (the virus that causes genital herpes) and the risk of HIV acquisition has been well-studied. A recent meta-analysis found that individuals with HSV-2 infection had a three-fold increase in their risk of HIV acquisition, and it has been estimated that approximately half of all HIV infections can be attributed to HSV-2.

Furthermore, it is known when HIV-positive individuals have episodes of symptomatic HSV-2 disease - genital herpes - these are longer and more severe than in HIV-uninfected individuals. Some studies have also found that infection with HSV-2 is associated with an increase in HIV viral load in genital fluids.

It has been suggested that individuals infected with HSV-2 could reduce their risk of HIV infection by taking ongoing suppressive anti-herpes therapy. Investigators from London and Tanzania therefore designed a 30-month randomised, placebo controlled trial to see if daily anti-herpes treatment consisting of a daily oral dose of 400mg of aciclovir reduced the risk of HIV infection.

A total of 820 HIV-negative women, all of whom were infected with HSV-2, were recruited to the study in a mining district of Tanzania. Women who worked in bars and guest houses were targeted for inclusion in the study because of their high risk of HIV due to “opportunistic sex work”.

The women were screened for HIV and other sexually transmitted infections at baseline and randomised to the aciclovir or placebo arms. They were followed up at three monthly intervals when they were provided with further study treatment packs, condoms and safer sex counselling. At follow-up, the women were also offered HIV testing.

Information about the importance of adherence was provided to the women, and to monitor adherence pill counts were conducted. In addition, there were two random urine tests to monitor aciclovir levels.

Women in the two arms of the study were well-matched at baseline, although women in the aciclovir arm were slightly more likely to report a history of transactional sex (40% versus 34%).

Study end-points were infection with HIV, pregnancy, or the completion of 30-months follow-up.

Approximately 60% of women completed the study. The investigators’ intent-to-treat analysis showed that a total of 8% of women seroconverted for HIV, with almost identical proportions of women in the aciclovir and placebo arms diagnosed with the infection. The HIV incidence rate was 4.29 per 100 person years in the aciclovir arm and 4.25 per 100 person years in the placebo arm.

An on-treatment analysis was also performed. Once again, there was no significant difference in HIV incidence in the aciclovir arm (4.46 per 100 person years) and the placebo arm (3.99 per 100 person years).

However, Dr Watson-Jones then presented data on adherence to aciclovir therapy. These data showed that approximately 50% of patients in the treatment arm had 90% or better adherence to treatment, with a further 19% taking between 75% and 90% of their pills. Women with 75% or better adherence to aciclovir therapy had an odds ratio of HIV infection of 0.58, but the confidence intervals meant that this reduction in risk was not statistically significant.

Disappointment with the study’s findings was expressed by Dr Watson-Jones. She speculated that poor adherence to therapy may have been a factor in the results and suggested that more intense follow-up (as often as every two weeks) could improve adherence and thereby help to reduce HIV incidence. It is, however, perhaps worth noting that adherence of 70% has been observed in trials examining other prevention technologies such as microbicides and pre-exposure prophylaxis, and the sub-optimal adherence seen in this aciclovir trial may be indicative of levels of adherence that would be achieved in a “real-world” setting.

Dr Watson-Jones and her team of investigators also conducted a randomised, placebo controlled trial involving HIV-positive women. They wished to determine the effect of daily aciclovir therapy on HIV viral load in genital secretions. These results will be presented later in the conference.

Anti-herpes simplex virus-2 (HSV-2) therapy with daily aciclovir does not protect women against infection with HIV, according to the results of a randomised controlled trial conducted in Tanzania presented to the Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Sydney on July 23^rd.

Dr Debby Watson-Jones, of the London School of Hygiene and Tropical Medicine, told the conference that almost identical HIV incidence was observed in the aciclovir and placebo arms of the study. However, approximately 50% of the women provided with acyclovir failed to achieve the target 90% adherence to their daily therapy, and when the investigators looked at their data again - controlling for adherence - they found a non-significant trend towards lower HIV incidence amongst women with optimum levels of adherence. Dr Watson-Jones suggested that poor adherence could have contributed to the disappointing results of the study

A separate study presented in the same session of the conference looked at the relationship between HSV-2 infection and HIV diagnoses amongst US military personnel between 2000 and 2004. This study revealed that infection with HSV-2 significantly increased the risk of HIV infection.

HSV-2, HIV and the US military

A study looking at the relationship between HSV-2 and HIV infection amongst US military personal was also presented to the conference. Mr C Bautista, of the Walter Reed Army Institute of Research, who presented the study suggested that its findings could have wider implications for public health and HIV prevention.

In 1986, a total of 2,800 US military personal were HIV-positive. By 2004, however, this had fallen to 242. A steady fall in HIV incidence in the US military was observed from the late 1980s to 1999, but from 2000 onwards HIV incidence amongst US service personal has increased and by 2004 stood at 0.2 per 1,000 person years.

At the same time, incidence of HSV-2 infection has increased from 1.25 per 1,000 person years in 1998 to 1.94 per 1,000 person years in 2002. Mr Bautista said there was “a silent epidemic of HSV” in the US military and wished to see if there was any link between increasing HIV and HSV incidence.

He and his colleagues therefore designed a case-controlled study. Each serving member of the US military diagnosed with HIV between 2000 and 2004 was matched with two members of the military testing HIV-negative as controls. Demographic data and infection with HSV-2 were compared.

The study involved 492 individuals with HIV and 984 controls. HSV infection was present in 30% of those diagnosed with HIV but only 10% of the controls.

Statistical analysis revealed a strong link between HSV-2 infection and diagnosis with HIV. In multivariate analysis, HSV-2 was associated with an adjusted odds ratio of HIV infection of 3.99 (95% confidence interval; 2.66 – 5.67).

The population attributable risk of HIV due to HSV-2 infection was 25%.

Approximately a quarter of individuals with HSV-2, regardless of their HIV infection status were African American. Although women comprise only 10% of the US military, 48% of those with HSV and HIV were women. No data were presented on sexual risk behaviour or on sexual orientation. Gay men and lesbians are effectively banned from serving in the US services, but data from the US Department of Veterans’ Affairs, the largest single provider of HIV care in the US, show that significant numbers of US military veterans with HIV report having sex with other men.

On the basis of these results, Mr Bautista concluded that there was a high HSV-2 prevalence amongst US military personal and that HSV-2 infection was strongly associated with a risk of HIV infection. He noted that the findings of his study were broadly in line with other research examining this issue.

Implications for public health and HIV prevention were outlined by Mr Bautista, including regular HIV and HSV-2 screening and the use of valaciclovir suppressive therapy in individuals diagnosed with HSV-2.