Genital Herpes

Antiviral therapy for human cytomegalovirus – Human Herpesviruses

Valaciclovir (Valtrex) 2 g twice daily for 1 day was recently approved in the United States for treatment of cold sores. HSV-2-targeted guanosine analogues are effective when given on a prophylactic basis, but do not completely eliminate recurrences, asymptomatic shedding or transmission. The role of chronic suppressive therapy in the management of genital herpes as well as its potential impact on transmission rates will also be discussed. This virus will remain in the nerve ganglia and then stay dormant until it is triggered by one or more factors. The study enrolled 1484 immunocompetent, heterosexual, monogamous couples in stable relationships where both partners were aware of the source partner’s infection and the source partner had symptomatic genital herpes. They all have the same mechanism of action. Examples include qualitative detection of viremia by PCR or antigenemia where the assay level of detection has been shown to be associated with a high risk of disease, or two consecutive samples PCR-positive.

Alternatively, if samples are processed by real-time quantitative PCR, then any value above a pre-determined cut-off should trigger antiviral intervention. The results of viral dynamic assessments can also be applied to this problem; patients at risk of disease can be identified by the absolute value of viral load found in the first PCR-positive sample, coupled with an assessment of individual viral dynamics by calculating the rate of increase from the last PCR-negative sample (Emery et al., 2000). All of these approaches work well in clinical practice and comparative studies are required to determine if any one of them is superior to the others. Results of published trials of licensed drugs defined according to these criteria are given in Table . An impressive array of enzymes and specificity factors install and remove complex histone posttranslational modifications that lay the foundation for recognition by families of effector proteins (histone readers”). Other agents such as interferon-alpha, acyclovir, valaciclovir and immunoglobulin, have also been evaluated although they were traditionally not thought to have useful anti-CMV activity. For the endpoint of CMV infection, Table  shows that, in addition to ganciclovir (Balfour et al., 1989; Cheeseman et al., 1979; Lui et al., 1992), interferon alpha (Cheeseman et al., 1979; Lui et al., 1992; Ljungman et al., 1992) and acyclovir (Lowance et al., 1999; Balfour et al., 1989; Prentice et al., 1994) have activity against CMV in vivo.

The only two studies not to show an effect were the two studies of immunoglobulin (Metselaar et al., 1989; Snydman et al., 1993). This implies that, if immunoglobulin has a role in the prophylaxis of CMV disease, it may not work by inhibiting CMV replication. For the endpoint of CMV disease, Table  shows that ganciclovir failed to demonstrate a significantly better resolution of established CMV disease than placebo (Reed et al., 1990). Part of this disappointing outcome may be attributed to the low dose (2.5 mg/kg t.i.d.) and/or short duration used (14 days) to treat gastrointestinal disease in stem cell transplant patients (Reed et al., 1990). Nevertheless, it illustrates the difficulty of treating established CMV disease and so argues that the other strategies, which aim to prevent CMV disease, should always be pursued in preference to waiting for disease to present. This is called tolerance. It also had a significant benefit when used in one (Goodrich et al., 1993) of two trials of prophylaxis after stem cell transplant; the second study (Winston et al., 1993) showed a strong trend in favor of GCV which just failed to reach conventional statistical significance.

Ganciclovir also significantly reduced CMV disease following prophylaxis given orally to liver transplant patients (Gane et al., 1997) and intravenously to heart transplant patients (Macdonald et al., 1995; Merigan et al., 1992). However, benefit after heart transplant was evident only in the low risk group, with no effect in the D+R− group of one study (Merigan et al., 1992), whereas the opposite outcome was seen in a second (Macdonald et al., 1995). This difference might result from the longer treatment course in the latter study, together with a design difference such that patients experiencing rejection were given additional doses of GCV. Prophylactic ACV significantly reduced CMV disease after renal transplant (Balfour et al., 1989), as did prophylactic valaciclovir (Lowance et al., 1999). In a prophylaxis trial after stem cell transplantation, acyclovir significantly decreased CMV viremia and showed a non-significant trend towards reduced CMV disease (Prentice et al., 1994). A trial of immunoglobulin prophylaxis showed reduced “CMV syndrome” in liver transplant recipients despite having no significant effect on CMV infection (Snydman et al., 1993). When I woke up the next morning and looked over she was awake and already staring at me.

CMV-specific immune globulin and a gH monoclonal antibody were ineffective in stem cell tranplant recipients (Boeckh et al., 2001; Bowden et al., 1991). Table  also summarizes the impact of these drugs on the indirect effects of CMV infection. The number of deaths in the solid organ transplant populations is too low to provide the statistical power to address this endpoint. After stem cell transplant, GCV significantly improved survival when used suppressively (Goodrich et al., 1991). However, when used prophylactically, no effect was seen (Goodrich et al., 1993; Winston et al., 1993). This was not a problem of small sample size and neither study demonstrated even a trend in favor of ganciclovir. The most likely explanations are that (ⅰ) some patients with viremia still received pre-emptive therapy (Goodrich et al., 1993) so reducing CMV-induced mortality in both arms (ⅱ) neutropenia induced by prophylactic GCV predisposed patients to succumb to bacterial or fungal superinfections, so mitigating the potential benefits of this drug.

The worst part was feeling I could never date guys again. This illustrates that, in prophylaxis, all patients are exposed to side-effects and that suppression or preemptive therapy, by limiting the number of patients exposed to the drug, can produce an enhanced therapeutic ratio. In contrast, ACV prophylaxis after stem cell transplant produced a survival benefit (Prentice et al., 1994), presumably because its more modest efficacy was not offset by serious toxicity. After renal transplant, VACV produced a marked reduction in biopsy-proven acute graft rejection corresponding to a 50% decrease in incidence among seronegative recipients at risk of primary infection (Lowance et al., 1999). The effects in seropositive recipients were smaller, implying that CMV (rather than another herpesvirus susceptible to the drug) is responsible for this indirect effect and that most CMV-induced graft rejection occurs in the subset of patients with primary infection. Following heart transplantation, GCV significantly reduced fungal infections (Wagner et al., 1995) and accelerated atherosclerosis (Valantine et al., 1999). Table  summarizes randomized studies which compared two anti-CMV strategies.

Boeckh et al. L’herpes è molto fastidiosa a skin pathology and unsightly, proprio come l’orzaiolo per l’occhio. Invasive bacterial and fungal infections were more common with GCV prophylaxis, resulting in similar mortality rates at day 400 (Boeckh et al., 1996). Humar et al. compared GCV based on a surveillance BAL at day 35 with antigenemia-guided preemptive therapy and found these two strategies equivalent in a small randomized trial (Humar et al., 2001). Reusser et al. compared foscarnet with GCV for preemptive therapy in stem cell transplant recipients (Reusser et al., 2002).

Survival without CMV disease was similar between the groups, however, GCV caused more neutropenia. Foscarnet was associated with more electrolyte imbalances but renal insufficiency was no different between the two groups. One trial by Winston et al. compared valacyclovir with ganciclovir prophylaxis in stem cell transplant recipients. The incidence of CMV disease was similar in both groups, however, the trial was not large enough to make meaningful conclusions (Winston et al., 2003). Another small trial by Winston et al. compared sequential intravenous and oral ganciclovir with intravenous ganciclovir for 3 months in D+/R− liver transplant recipients (Winston and Busuttil, 2004).

The incidence of CMV disease was not statistically different between the groups. In liver transplant patients, prophylaxis with GCV is superior to prophylaxis with ACV (Winston et al., 1995). A large randomized double-blind trial of valganciclovir versus oral GCV in D+/R− solid organ transplant recipients showed similar rates of CMV disease with the two compounds (Paya et al., 2004). Neutropenia was observed more frequently with valganciclovir. In another randomized trial in AIDS patients with CMV retinitis valganciclovir showed similar activity to intravenous ganciclovir for treatment of retinitis (Martin et al., 2002). Additional randomized trials compared different methods of detecting CMV in blood for preemptive therapy and found equivalence between antigenemia and pp67 mRNA (Gerna et al., 2003a,b) and IE mRNA (Gerna et al., 2003a,b). An earlier randomized trial by Einsele et al.

established that PCR-based detection by CMV viremia is superior to culture-based detection of viremia for initiation of preemptive therapy (Einsele et al., 1995). A comparison of ganciclovir plus foscarnet (each at half dose) compared to full dose ganciclovir showed that these two drugs are not synergistic in humans when used for pre-emptive therapy (Mattes, 2004).