|Year : 2006 | Volume
| Issue : 1 | Page : 8-12
|Management of genital herpes infections in HIV infected patients
S Samraj, R Patel
Department of Genito-Urinary/HIV Medicine. Southampton University Hospitals NHS Trust, Brinton's Terrace, Southampton, Hampshire SO 14 OYG, United Kingdom
Department of Genito-Urinary/HIV Medicine. Southampton University Hospitals NHS Trust, Brinton's Terrace, Southampton, Hampshire SO 14 OYG
Source of Support: None, Conflict of Interest: None
Keywords: Herpes, Genetal herpes, HIV, AIDS, Management
|How to cite this article:|
Samraj S, Patel R. Management of genital herpes infections in HIV infected patients. Indian J Dermatol 2006;51:8-12
| Introduction|| |
Clinical presentation and management of genital herpes with HIV coinfection is different in a number of ways. Firstly, episodes of recurrent genital HSV infections are often more frequent and persistent. In advanced HIV disease there may be a failure to clear virus from the skin during lesional recurrences and dissemination is more frequent. Secondly there is some evidence to suggest an increased risk of HIV transmission during clinical and subclinical HSV recurrences.
Drug therapy of HSV disease is a major problem in HIV immunosuppression. There is significant risk of single and multi-drug resistance. In addition previously quiescent HSV disease can reactivate during immune reconstitution with HAART therapy., There is little evidence to demonstrate clearly the efficacy of anti-HSV therapy in HIV-positive patients. Only some of the first line agents such as aciclovir (ACV), valaciclovir (VACV) and famciclovir (FAMCV) have been shown to be effective in limited settings. Strategies for the effective use of these agents to prevent the development of resistant disease have not been established. Studies are currently underway to determine the impact of HSV therapy in limiting onward HIV transmission., In resistant disease a number of other compounds have also been used. Reasonably good data exists for foscarnet, whilst the efficacy of the nucleotide cidofovir is still under review.
| Mechanism of Action of Antiviral Drugs|| |
There are 3 major medications (ACV, FAMCV and VACV) used to treat genital herpes infections whether the infection is due to HSV-1 or HSV-2. The drugs differ somewhat in their chemical structure.
ACV is an acyclic analogue of the nucleoside, guanosine. ACV diffuses passively across most animal cell membranes. Within cells, ACV is phosphorylated at a rapid rate by virus-specific thymidine kinase (TdK), but is slowly phosphorylated by the host TdK. ACV monophosphate cannot pass out of the cytoplasm into the extra-cellular spaces. The affinity of ACV for thymidine kinase produced by normal host cells is approximately 250 times less than for the thymidine kinase encoded by HSV. This selective affinity results in the activation and concentration of ACV in virus-infected cells. Once ACV is converted into ACV monophosphate by the viral thymidine kinase, it is further converted to ACV triphosphate by cellular kinases [Figure - 1]. ACV triphosphate competes with deoxyguanosine triphosphate for binding to the HSV DNA polymerase. It has much lower affinity for cell DNA polymerases. When it is incorporated into the viral DNA, ACV prevents further elongation of the chain. Such termination of the growing DNA chain is immediate and irreversible. To conclude, ACV triphosphate is a substrate for and a preferential inhibitor of viral, rather than cellular, DNA polymerase. ACV has no effect on latency.
FAMCV is rapidly converted to the active compound, penciclovir (PCV), by enzymes in the intestinal wall and liver. PCV passes into infected cells and is similarly phosphorylated by the viral thymidine kinase to its monophosphate form. This is then converted to PCV triphosphate, which competes with deoxyguanosine triphosphate to inhibit viral DNA polymerase activity by the same mechanism as ACV. Some differences exist between this process and that of ACV. Since PCV-TP has two -OH groups, same DNA chain elongation tends to continue; however, DNA formation is terminated within 1-2 additional base insertions.
VACV is rapidly and nearly completely converted to ACV by intestinal and hepatic metabolism. Its absorption is not limited (as for ACV) and allows a linear bioavailability profile.
Foscarnet is a pyrophosphate analogue that acts as a noncompetitive inhibitor of viral DNA polymerase. Inhibition of DNA polymerase results in inhibition of pyrophosphate exchange, which prevents elongation of the DNA chain. Foscarnet does not require activation by thymidine kinase.
Cidofovir (CDV) is a phosphonomethylether derivative of cytosine with potent in vitro and in vivo activity against a broad spectrum of herpes viruses. It differs from most other nucleoside analogues in that there is no sugar ring and, because of the phosphonate group, it undergoes only two additional phosphorylations in order to be metabolically equivalent to nucleoside triphosphates. CDV is phosphorylated by cellular enzymes, therefore metabolism is not affected by HSV infection. HSV strains with altered or deleted thymidine kinase (TK) activity, which make up the vast majority of ACV-resistant HSV strains have increased susceptibility to CDV.
| Methods of Resistance Testing|| |
Antiviral methods for the determination of susceptibility in HSV include the plaque reduction assay (PRA), dye uptake (DU), CPE (cytopathic effect) inhibition, virus yield reduction, inhibition of specific immuno-fluorescence and DNA hybridization.
PRA has classically been considered to be the reference method of choice. However, all these methods are tedious and time consuming.
The susceptibility of HSV to ACV can be determined by two rapid assays: a rapid cytopathic effect inhibitory assay (Rapid CIA) and a rapid dye uptake assay (Rapid DUA). These rapid tests, unlike conventional assays, are able to provide susceptibility results within 3 days after virus has been isolated from a clinical specimen and could thus play a direct role in therapeutic decisions.
| Management of Initial Genital Herpes|| |
Acquisition episodes of HSV can present even in HIV-negative individuals with a severe and prolonged illness but these would be expected to resolve spontaneously. In HIV-positive patients the skin lesions can become chronic and multifocal and at times this may be associated with systemic symptoms such as fever, malaise and headache. It is important to treat all cases of suspected initial genital herpes with appropriate therapy. Intravenous ACV has been approved for use in the immunocompromised,, but there is a lack of studies specifically in HIV-positive patients. Controlled trials of oral agents (ACV 200mg 5 times daily, VACV 1g bd and FAMCV 250-750 mg tds all for 10 days) have also been shown to be effective in immunocompetent patients with less severe initial disease. ,,, Various doses of these agents are recommended in guidelines for 5-10 days in the immunocompromised. Such regimens may well be appropriate in HIV positive patients. The recommendations are that therapy be continued until all lesions have re-epithelialised and some agents be given at higher dose (ACV 400 mg 5 times a day).
| Recurrent Genital Herpes|| |
Two important factors underlie reactivation in HSV-HIV co-infection: the underlying HIV RNA viral load and the degree of immuno-suppression. At CD4 count <100 cells/ml the body's cell mediated immune mechanisms are less likely to clear HSV from the skin resulting in the development of chronic persistent ulceration. In treating recurrent HSV infection in HIV positive patients it is important to optimise the treatment of the underlying immunosuppression through HAART. Two strategies exist for the therapy of recurrent genital herpes: episodic intermittent therapy or continuous suppressive therapy.
| Episodic Therapy for Recurrent Genital Herpes|| |
Two controlled studies of episodic therapy have been conducted in HIV-positive patients. One study compared the efficacy of randomly assigned patient-initiated VACV at 1g BD and ACV at 200mg five times daily, both for 5 days. ,, The median CD4 count was 240-cells/ml and treatment was started within 12 hours of symptoms. ,, This study did not reveal any difference in time to disease resolution between the two drug regimes. (Median time to healing was 5 days).
The second study looked at a population of 157 patients who were randomised to receive either FAMCV 500 mg bd or ACV 400 mg x 5 for 7 days within 48 hours of lesion development. The median CD4 count was > 200 cells/ml for the study population. Both groups had cessation of viral shedding in 2 days, symptom resolution in 4 days and complete lesional healing in 7 days.
Both these studies suggest that the median time to healing for HIV positive patients may be between 5-7 days, which is somewhat longer than for immunocompetent individuals.
In summary [Table - 1], the data support the episodic use of ACV 200-400 mg x 5 daily, FAMCV 500 mg bd daily and VACV 1g bd for 5-7 days. It is important to initiate therapy at the earliest opportunity and ideally should be patient-initiated. Short-course therapy (3 days or less) cannot be recommended for HIV positive patients.
| Continuous Suppressive Therapy|| |
Continuous suppressive therapy is indicated in recurrent HSV disease that is frequent, severe or complicated. There is a theoretical reduction in the risk of HIV transmission and the advantage of improved viral RNA control with this approach.
Suppressive therapy should only be started after effective antiviral therapy (at one of the above doses) has settled an acute episode. The studies of suppressive therapy for HSV disease in HIV-positive patients have tended to use higher doses of drugs when compared to those used in immunocompetent individuals.
Current evidence indicates that VACV is the best agent for use in HIV positive patients. A randomised placebo controlled 6-month study of VACV in HIV-positive patients with a history of 4 or more recurrences per year showed a high level of disease control for VACV (time to first recurrence 6 months) compared to 59 days in the placebo group. A larger 1-year study in patients with milder disease has demonstrated the superiority of VACV 500mg bd to 1g od and a trend to superiority over ACV 400mg bd. Patient tolerability and safety of VACV were satisfactory from both these studies. FAMCV has been studied in a small sample of HIV-positive subjects in an 8-week placebo controlled crossover trial. The outcome was that treatment reduced the number of symptoms and viral shedding. The current published data do not support the most frequently used ACV at the conventional doses of 400 mg bd or tds. However, two studies from the pre-HAART era have shown the efficacy of ACV at 800mg qds compared to placebo (38% and 29% reduction in disease frequency respectively).
| Management of Recurrences on Therapy|| |
Evidence suggests that repeated breakthrough recurrences should be treated even when patients are on suppressive therapy., Dividing the total daily dose of 800mg ACV to bd or qds regime has been shown to be beneficial in controlling breakthrough episodes for immunocompetent patients and therefore may be effective for HIV-positive patients. But this increases the complexity of the treatment for patients who are already on HAART. Increasing the dose of drugs then seems to be the best alternative. But theoretically this regime may not be any more efficacious than the usual therapeutic doses as the dose-response curve for ACV, FAMCV, and VACV are relatively flat.
[Figure - 2]
| Management of Suspected Aciclovir Resistant Disease|| |
The first case of resistance to ACV leading to treatment failure was reported in 1982. Development of resistance to ACV is more frequent in HIV infected individuals when compared to the immunocompetent population. Recently a CDC surveillance study reported 5.3% incidence of ACV resistant HSV strains in HIV-positive patients.,
Several mechanisms exist for the development of ACV resistance. The most common defect is a mutation in the gene encoding HSV thymidine kinase (TK), resulting in the absence of TK or TK with markedly reduced affinity for ACV. TK catalyses the synthesis of ACV-monophosphate through which the drug acts in virally infected cells. Therefore, diminished activity or absence of TK results in resistance to, or reduced potency of ACV. VACV and FAMCV are activated by the same mechanism and hence it would appear that nucleoside resistance would extend to them as well. A second mechanism of resistance is by an alteration in the substrate specificity of the viral DNA polymerase. This may be overcome by increasing the dose of ACV as reported in a number of cases.
ACV resistant HSV infections are often found in number of sites, the most common being the perirectal area. The lesions are typically painful and disfiguring and tend to be deep confluent ulcers with hypertrophic areas around the edges. If a standard dose of oral ACV fails to demonstrate a clinical response after 3-5 days of therapy, the dose should be doubled or the drug should be administered intravenously to overcome the possibility of poor oral availability. Resistance should be assumed if this fails to produce a clinical response after 7 days. Testing the HSV isolate from the lesion for resistance is the ideal option, however few clinics have access to this facility and current assays can take upto 2 weeks to derive the results.
The treatment of choice is either to use high dose intravenous ACV in an attempt to overcome thymidine kinase deficiency (this requires serum ACV level monitoring) or to use intravenous foscarnet (40 mg/kg every 8 hours). Topical trifluorothymidine liquid used alone or in combination with interferon alpha has been reported to be of benefit, and cidofovir, a monophosphorylated nucleotide analogue, has been reported to provide significant benefit in terms of lesion healing, virological effects and pain reduction when used intravenously or as a gel. Two studies have demonstrated some success with topical foscarnet., There is lack of sufficient data to confirm the efficacy and safety of these agents. Any therapy, which appears to be working, should be continued until full re-epithelisation of all lesions occurs.
ACV resistant HSV disease can be very challenging to treat and the prognosis essentially depends on whether or not the underlying immune status can be improved.
| Conclusions|| |
The management of genital herpes in HIV-infected patients can be complex. Effective treatment of genital herpes not only involves anti-herpes therapy but effective control of the HIV viral load with HAART therapy. Resistance to anti-viral treatment is much more common than in immunocompetent patients and a clear need exists for novel therapies to manage resistant HSV disease.
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[Figure - 1], [Figure - 2]
[Table - 1]
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