Opportunistic Infections and Coinfections: Focus on Fungi and Hepatitis

http://www.medscape.com/viewarticle/443353

William G. Powderly, MD   

One of the most prominent features of the highly active antiretroviral therapy (HAART) era has been the positive impact on opportunistic infections (OIs). In particular, among patients with good immunologic and virologic responses to HAART, it has proved possible to stop primary prophylaxis and maintenance therapy in patients with previously active infections. Indeed, the guidelines issued by the US Public Health Service and the Infectious Diseases Society of America currently recommend that following a rise in CD4+ cell count and control of viral replication, one can stop primary and secondary prophylaxis for virtually all OIs.^[1]

Most of the supporting data come from cohort studies and some prospective studies that examined the most common OIs: Pneumocystis carinii pneumonia, disseminated Mycobacterium avium complex infection, and cytomegalovirus retinitis. However, less information has been available for fungal infections, and some experts have expressed reservations as to whether it is indeed safe to stop secondary prophylaxis in patients with prior systemic infections. Three studies presented at the XIV International AIDS Conference in Barcelona added additional support for current recommendations.

Opportunistic Fungal Infections: Safety of Discontinuing Prophylaxis?

Two studies^[2,3] addressed maintenance therapy for cryptococcal meningitis. The first study,^[2] by investigators in Thailand, was a prospective randomized trial with patients who had had an episode of cryptococcal meningitis and who had responded to antiretroviral therapy. All patients had received maintenance antifungal therapy with fluconazole and antiretroviral therapy with zidovudine, lamivudine, and efavirenz for 48 weeks. Patients who had had CD4+ cell counts > 100 cells/mm³ and plasma HIV-1 RNA levels < 400 copies/mL for at least 3 months were then randomized either to stop or to continue taking fluconazole. Of the original 49 patients enrolled, 42 met these immunologic and virologic criteria by 48 weeks. Of these 42, 20 were randomized to stop prophylaxis and remained disease free, with a median follow-up of 12 weeks.

The second study^[3] was a retrospective cohort of 56 patients from European, US, and Latin American centers. All patients had had cryptococcal infection with a CD4+ cell count < 100 cells/mm³ and had received fluconazole maintenance therapy and HAART. Fluconazole therapy had been stopped after the CD4+ cell count had risen to > 100 cells/mm³ after at least 2 months of HAART. The median time of follow-up was 21 months (range, 3-56 months), and the median duration of HAART before cessation of fluconazole use was 29 months (range, 2-62 months). Of the 56 patients, 3 relapsed, giving an overall relapse rate of 2.68 per 100 patient-years of follow-up (95% confidence interval, 0.5-7.24). Of note, all the relapses were atypical (central nervous system cryptococcoma, sterile meningitis, lymphadenitis), and in 2 cases there was evidence of immunologic failure (falling CD4+ cell count) before the clinical relapse.

Another study^[4] examined the similar situation of stopping maintenance therapy for disseminated histoplasmosis. Researchers in Argentina studied 39 patients who had again received HAART after antifungal therapy. At the time of discontinuation, they had received a median of 19 months of antiretroviral therapy and a median of 24 months of itraconazole therapy. The median CD4+ cell count at the time of discontinuation was 266 cells/mm³. As with cryptococcal infection, discontinuation of maintenance therapy appeared safe, with no relapses after a median of 20 months of follow-up (range, 1-52 months).

Thus, one can conclude from these studies that patients with invasive fungal infections whose CD4+ cell counts recover to at least 100 cells/mm³ can discontinue maintenance therapy. Caution should be retained in symptomatic patients, those who have other evidence of immune dysfunction, and those in whom viral replication is not completely suppressed. In the latter case, it may be possible to stop prophylaxis if the CD4+ cell count is maintained at at least 100 cells/mm³, but patients will need to be monitored carefully because the continuing viral replication may eventually lead to immunologic failure.

Primary Prophylaxis for Fungal Infections in the Developing World?

Although fluconazole has been shown to be effective as primary prophylaxis for invasive fungal infections in the developed world, it is not generally recommended because of the relatively low incidence of such infections and the lack of a benefit on survival. However, the situation could be quite different in the developing world, especially where cryptococcal infection is highly prevalent.

Preliminary data from a small randomized trial of primary prophylaxis with fluconazole (400 mg once weekly) in Thailand showed no difference in the incidence of fungal infections but a survival difference that was marginally significant.^[5] A total of 90 patients with CD4+ cell counts < 100 cells/mm³ were enrolled, of whom 44 received fluconazole and 46 were assigned to placebo. There were 5 invasive fungal infections in the fluconazole group and 9 in the placebo group, a difference that was not statistically significant. Of interest, there were 2 deaths in the fluconazole group compared with 9 in the placebo arm, giving death rates of 2.7% and 11.7%, respectively. This is a preliminary study, and it is too small to instill confidence that the finding is real, but this observation supports large randomized trials of primary prophylaxis in areas such as South and Southeast Asia and sub-Saharan Africa, where the incidence of cryptococcal infection is very high.

More Rapid Progression of Fibrosis in Hepatitis C Virus-HIV Coinfection

As at other meetings in recent years, hepatitis B virus and hepatitis C virus (Hepatitis C Virus) coinfection was prominently reported in Barcelona. Many presentations reported the frequency of liver disease--and hepatitis in particular--as a cause of morbidity and mortality in HIV infections. However, as several delegates pointed out, there is little evidence that the mortality from liver disease is increasing; rather, as the mortality from OIs decreases, liver disease assumes a more prominent role as a cause of hospitalization and death.

A study^[6] from London confirmed previous French data,^[7] indicating that Hepatitis C Virus-associated liver fibrosis progresses more rapidly in patients who are coinfected with HIV and Hepatitis C Virus compared with those infected with Hepatitis C Virus alone. The study enrolled 128 Hepatitis C Virus-positive individuals, 33 of whom were also infected with HIV. Most were male (71%) and injection drug users (81%). All patients had undergone biopsies, and the date of Hepatitis C Virus acquisition was estimated based on the year they started injecting drugs or received blood products. The progression rate of liver fibrosis was higher in coinfected patients, with a median progression rate of 0.181 units per year compared with 0.121 units per year in the HIV-negative patients. These data were used to estimate time to cirrhosis: the estimated time from initial infection with Hepatitis C Virus to established cirrhosis in coinfected patients was 21 years compared with 31 years in patients infected with Hepatitis C Virus alone. This difference was supported by data from a small number of patients in whom serial biopsy specimens were available. Thus, HIV should be added to the list of factors known to accelerate progression to cirrhosis, such as male sex, older age, and alcohol use.

These findings, viewed alongside the evidence that therapy for Hepatitis C Virus slows progression to cirrhosis even when it does not control viral replication, should encourage more and earlier treatment of Hepatitis C Virus in coinfected patients. The practical problem we face is that interferon-based therapy is most effective in coinfected patients when initiated at CD4+ cell count levels > 500 cells/mm³, but it is increasingly unusual for HIV-infected patients to be diagnosed this early in the disease.

Pegylated vs Standard Interferon Plus Ribavirin in Hepatitis C Virus and HIV Coinfected Patients

Few new data on treatment of Hepatitis C Virus coinfection were presented. However, 48-week results from a large randomized French trial^[8] comparing once-weekly pegylated interferon 2-alfa (1.5 mcg/kg weekly) vs thrice-weekly standard interferon 2-alfa (3 mU 3 times weekly) were presented. Each was given with ribavirin, 800 mg/day. The 48-week data were available for 143 patients in the pegylated interferon group and 152 in the standard interferon group. The proportions with a virologic response (undetectable Hepatitis C Virus DNA) at 48 weeks were 37% in the pegylated arm and 24% in the standard arm. Approximately two thirds of the patients had Hepatitis C Virus genotype 1 or 4. Pegylated interferon had more adverse effects but was reasonably well tolerated.

It is important to emphasize that this was an interim analysis. The primary end point is the sustained viral response (ie, undetectable Hepatitis C Virus DNA 6 months after the end of the study), and we must wait until those data are available before being sure of the true effectiveness of pegylated interferon in coinfected patients. However, viewed with the data from ACTG 5071^[9] presented at the 9th Conference on Retroviruses and Opportunistic Infections in February 2001 and the evidence from treatment trials in patients infected only with Hepatitis C Virus,^[10,11] it seems appropriate to recommend pegylated interferon as standard treatment for coinfected patients.

Nevirapine and Hepatitis

Doug Mayers^[12] from Boehringer Ingelheim presented an interesting analysis of data pooled from all of the sponsored studies of nevirapine. The overall incidence of hepatitis (defined as abnormal transaminases > 5 times the upper limit of normal) was 8.8%. One syndrome recognized in particular was rash-associated hepatitis, which occurs early after the administration of nevirapine and is probably a hypersensitivity reaction. Essentially all cases described occurred within 6 weeks of starting nevirapine therapy, and most resolved rapidly on withdrawal. Rechallenge is not recommended, although other nonnucleoside reverse transcriptase inhibitors appear not to cross-react. Risk factors for the development of the syndrome included female sex (relative risk [RR], 3.2) and CD4+ cell counts > 250 cells/mm³ in female patients (RR, 9.8) or > 400 cells/mm³ in male patients (RR, 6.4). The role of underlying viral hepatitis in predisposing patients to this or other nevirapine-associated liver toxic effects could not be assessed. In too many older trials, infection with either hepatitis B virus or Hepatitis C Virus was not routinely determined--something that should not be allowed to occur in future studies of antiretroviral therapy.

References

1. Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among HIV-infected persons---2002: recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep. 2002;51(RR08):1-46.
2. Vibhagool A, Sungkanuparph S, Mootsikapun P, et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients treated with HAART: a prospective multicenter randomized study. Program and abstracts of the XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain. Abstract ThPeB7292.
3. Mussini C, Pezzotti P, Martinez E, et al. Discontinuation of maintenance therapy for cryptococcal meningitis in patients treated with HAART: a multicentre observational study. Program and abstracts of the XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain. Abstract ThPeB7287.
4. Sued O, Abusamra L, Helou R, et al. Discontinuation of maintenance therapy for disseminated histoplasmosis: a study of 39 patients. Program and abstracts of the XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain. Abstract ThPeC7476.
5. Chetchotisakd P, Sungkanuparph S, Thinkhamrop B, Mootsikapun P, Boonyaprawit P. A prospective multicenter randomized double-blind placebo controlled trial of primary cryptococcal meningitis prophylaxis in Thailand with a survival benefit. Program and abstracts of the XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain. Abstract ThPeB7294.
6. Mohsen AH, Taylor C, Portmann B, et al. Progression rate of liver fibrosis in human immunodeficiency virus and hepatitis C virus coinfected patients, UK experience. Program and abstracts of the XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain. Abstract MoOrB1057.
7. Benhamou Y, Bochet M, Di Martino V, et al, The Multivirc Group. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. Hepatology. 1999;30:1054-1058.
8. Perronne C, Carrat F, Bani Sadr F, et al. RIBAVIC trial (ANRS HC02): a controlled randomized trial of pegylated-interferon alfa-2b plus ribavirin vs interferon alfa-2b plus ribavirin for the initial treatment of chronic hepatitis C in HIV co-infected patients: preliminary results. Program and abstracts of the XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain. Abstract LbOr16.
9. Sherman KE, Horn P, Rouster S, Peters M, Koziel M, Chung R. Hepatitis C Virus RNA kinetic response to PEG-interferon and ribavirin in HIV co-infected patients. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, Washington. Abstract 122.
10. Lindsay KL, Trepo C, Heintges T, et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology. 2001;34:395-403.
11. Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122:1303-1313.
12. Stern J, Lanes S, Love J, Robinson P, Imperiale M, Mayers D. Hepatic safety of nevirapine: results of the Boehringer Ingelheim Viramune® Hepatic Safety Project. Program and abstracts of the XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain. Abstract LbOr15.