Year : 2006 | Volume
: 51 | 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«SQ»s Terrace, Southampton, Hampshire SO 14 OYG
|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
|How to cite this URL:|
Samraj S, Patel R. Management of genital herpes infections in HIV infected patients. Indian J Dermatol [serial online] 2006 [cited 2022 May 18 ];51:8-12
Available from: https://www.e-ijd.org/text.asp?2006/51/1/8/25177
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 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.
Management of Suspected Aciclovir Resistant Disease [Figure 2]
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.
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.
|1||Quinnan GV, Masur H, Rook AH, Armstrong G, Frederick WR, Epstein J et al. Herpes virus infections in the acquired immune deficiency syndrome. JAMA 1984; 252:72-7.|
|2||Barton S,Celum C, Shacker TW.The Role of anti HSV therapeutics in the HIV infected host and in controlling the HIV epidemic Herpes 2005; 12 (1):15-22.|
|3||Reyes M, Shaikh N, Graber J et al. Aciclovir-resistant genital herpes among persons attending sexually transmitted disease and immuno-deficiency virus clinics. Arch Intern Med 2003; 163:76-80.|
|4||Price P, Mathiot N, Krueger R et al .Immune dysfunction and immune restoration disease in HIV patients given highly active antiretroviral therapy. J Clin Virol, 2001; 22:279-87.|
|5||Schacker T, Zeh J, Hu H, Shaughnessy M, Corey L. Changes in plasma human immunodeficiency virus type 1 RNA associated with herpes simplex virus reactivation and suppression. J Infect Dis 2002; 186(12): 1718-25.|
|6||Gray RH, Wawer MJ, Brookmeyer R, Sewankambo NK, Serwadda D, Wabwire-Mangen F, Lutalo T, Li X, vanCott T, Quinn TC; Rakai Project Team. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001; 357(9263): 1149-53.|
|7||Manuel Cotarelo,Antonio Tenorio and Emilio Bouza.Cytopathic effect inhibition assay for determining the in-vitro susceptibility of HSV to antiviral drugs Journal of Antimicrobial Chemotherapy 1999; 44:705-8.|
|8||Maier JA, Bergman A, Ross MG. Acquired immuno-deficiency syndrome manifested by chronic primary genital herpes. Am J Obstet Gynecol 1986; 155:756-8.|
|9||Corey L, Fife KH, Benedetti JK, Winter CA, Fahnlander A, Connor JD et al. Intravenous aciclovir for the treatment of primary genital herpes. Ann Intern Med 1983; 98:914-921. |
|10||Myers JD, Wade JC, Mitchell CD et al . Multicenter collaborative trial of intravenous aciclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host. Am J Med 1982; 73:229-35.|
|11||Mertz GJ, Critchlow CW, Benedetti J, Reichman RC, Dolin R, Connor J et al. Double-blind, placebo-controlled trial of oral aciclovir in first episode genital herpes simplex virus infection. JAMA 1984; 252:1147-51.|
|12||Fife KH, Barbarash RA, Rudolph T, DeGregorio B, Roth R. Valaciclovir versus aciclovir in the treatment of first episode genital herpes infection. Results of an international, multicenter, double-blinded, randomised clinical tial. Sex Transm dis 1997; 24:481-6.|
|13||Loveless M, Sacks SL, Harris JRW. Famciclovir in the management of first episode genital herpes. Infect dis Clin Pract 1997; 6 (Suppl 1): S12-S16.|
|14||Augenbraun M, Feldman J, Chirgwin K, Zenilman J, Clarke L, De Hovitz J et al. Increased genital shedding of herpes virus type 2 in HIV-seropositive women. Ann Intern Med 1995; 123:845-7.|
|15||Reichman RC, Badger GJ, Mertz GJ, Corey L, Richman DD, Connor JD et al . Treatment of recurrent genital herpes simplex infections with oral aciclovir. JAMA 1984; 251:2103-2107.|
|16||Spruance SL, Tying SK, DeGregorio B, Miller C, Beuntner K. A large-scale placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent genital herpes. Arch Intern Med 1996; 156:1729-36.|
|17||Sacks SL, Aoki FY, Diaz-Mitoma F, Sellors J, Shafran SD. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. JAMA 1996; 276:44-9.|
|18||Leone PA, Trottier S, Miller JM. The International Valaciclovir Study Group. A comparison of oral valaciclovir 500mg twice daily for three or five days in the treatment of recurrent genital herpes (abstract). International Congress of Infectious Diseases, Boston, USA, 1998.|
|19||Strand A, Patel R, Wulf HC, Coates KM; International Valaciclovir HSV Study Group. Aborted genital herpes simplex virus lesions: findings from a randomised controlled trial with valaciclovir. Sex Transm Infect. 2002; 78(6): 435-9.|
|20||Wald A, Carrell D, Remington M, Kexel E, Zeh J, Corey L. Two-day regimen of aciclovir for treatment of recurrent genital herpes simplex virus type 2 infection. Clin Infect Dis. 2002; 34(7): 944-8.|
|21||Roamnowski B, Aoki FY, Martel AY, lavender EA, Parsons JE, Saltzman RL. Efficacy and safety of famciclovir for treating mucocutaneous herpes simplex infection in HIV-infected individuals. AIDS 2000; 14:1211-17.|
|22||Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, Douglas JM Jr, Paavonen J, Morrow RA, Beutner KR, Stratchounsky LS, Mertz G, Keene ON, Watson HA, Tait D, Vargas-Cortes M; Valacyclovir HSV Transmission Study Group. Once-daily valaciclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004; 350(1): 11-20.|
|23||Youle MS, Gazzard BG, Johnson MA, Cooper DA, Hoy JF, Busch H et al. Effects of high-dose oral aciclovir on herpes virus disease and survival in patients with advanced HIV disease: a double-blind, placebo-controlled study. AIDS 1994; 8:641-9.|
|24||Conant MA, Schacker TW, Murphy RL, Gold J, Crutchfield LT, Crooks RJ; International Valaciclovir HSV Study Group. Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials. Int J STD AIDS. 2002; 13(1): 12-21.|
|25||DeJesus E, Wald A, Warren T, Schacker TW, Trottier S, Shahmanesh M, Hill JL, Brennan CA; Valaciclovir International HSV Study Group. Valaciclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J Infect Dis. 2003; 188(7): 1009-16. Epub 2003 Sep 10. Erratum in: J Infect Dis. 2003; 188(9): 1404.|
|26||Cooper DA, Pehrson PO,Pedersen C, Moroni M, Oksenhendler E, Rozenbaum W et al . The efficacy and safety of Zidovudine alone or as co therapy with acyclovir for the treatment o patients with AIDS and AIDS-related complex: a double blind, randomised trial. AIDS 1993; 7:197-207.|
|27||Schacker T, Hu HL, Koelle DM, Zeh J, Saltzman R, Boon R, Shaughnessy M, Barnum G, Corey L. Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons. A double blind, placebo-controlled trial. Ann Intern Med 1998; 128(1): 21-8.|
|28||Mindel A, Faherty A, Carney O, Patou G, Freris M, Williams P. Dosage and safety of long term suppressive aciclovir therapy for recurrent genital herpes. Lancet 1988; 1:926-8.|
|29||Diaz-Mitoma F, Sibbald RG, Shafran SD, Boon R, Saltzman RL. Oral famciclovir for the suppression of recurrent genital herpes; a randomised controlled trial. JAMA 1998; 280:887-92.|
|30||Mertz GJ, Loveless MO, Levin MJ, Kraus SJ, Fowler SL, Goade D et al. Oral famciclovir for the suppression of recurrent genital herpes simplex virus infection in women. Arch Intern med 1997; 157:343-49.|
|31||Parris D, Harrington JE. Herpes simplex virus variants resistant to high concentrations exist in clinical isolates. Antimicrob Agents Chemother 1982; 22:71-7.|
|32||Englund JA, Zimmerman ME, Swierkosz EM, Goodman JL, Scholl DR, Balfour HH. Herpes simplex virus resistant to aciclovir. A study in a tertiary care center. Ann Intern Med 1990; 112:416-22.|
|33||Christophers J, Clayton J, Craske J, et al. Survey of resistance of herpes simplex virus to aciclovir in Northwest England. Antimicrob Agents Chemother 1998;42:868-72.|
|34||Patel R,Baron SE, Brown D et al .Management of genital herpes European Guidelines.Int J STD AIDS 2001;12(Suppl 3):34-9.|
|35||Hill EL, Hunter GA, Ellis MN. In vitro and in vivo characterization of herpes simplex virus clinical isolates recovered from patients infected with human immunodefieciency virus, Antimicrob Agents Chemother 1991; 35:2322-28.|
|36||Engel JP, Englund JA, Fletcher CV, Hill EL. Treatment of resistant herpes simplex virus with continuous -infusion aciclovir. JAMA 1990; 263: 1662-64.|
|37||Scoular A, Barton S. therapy for genital herpes in immunocompromised patients; a national survey. The Herpes Simplex Advisory Panel. Genitourin Med 1997; 73(5): 391-3.|
|38||Birch CJ, Tyssen DP, Tachedjian G, Doherty R, Hayes K, Mijch A et al. Clinical effects and in vivo studies of trifluorothmidine combined with interferon-a for the treatment of drug-resistant and sensitive herpes simplex virus infections. J Infect Dis 1992; 166: 108-12.|
|39||Kessler HA, Hurwitz S, Farthing C, Benson CA, Feinberg J, Kuritzkes DR et al. Pilot study of topical trifluridine for the treatment of aciclovir-resistant mucocutaneous herpes simplex disease in patients with AIDS (ACTG 172). J Acquir Immune Defic Syndr 1996; 12:147-52..|
|40||Lalezari J, Schacker T, Feinberg J, Gathe J, Lee S, Cheung T et al. A randomised, double-blind placebo-controlled trial of cidofovir gel for the treatment of aciclovir-unresponsive mucocutane-ous herpes simplex virus infection in patients with AIDS. J Infect Dis 1997; 176: 892-98.|
|41||Javaly K, Wohlfeiler M, Kalyjian R, Klein T, Bryson Y, Grafford K et al. Treatment of mucocutaneous herpes simplex infections unresponsive to aciclovir with topical foscarnet cream in AIDS patients: a phase I/II study. J Acquir Immune Defic Syndr 1999; 21:301-6.|
|42||Barton SE, Munday PE, Kinghorn GR et al. Topical treatment of recurrent genital herpes simplex virus infections with trisodium phosphonoformate (foscarnet); double blind, placebo controlled multicentre study. Genitourin Med 1986; 62:247-50.|