Visceral Leishmaniasis Relapses: Don’t Lose HAART

Abstract & Commentary

Synopsis: Despite some initial controversy, it appears that HIV-infected patients with relapses of visceral leishmaniasis have higher levels of HIV-RNA viral loads and lower CD4+ counts than those without relapses. Non-compliance with HAART regimens and intravenous drug use possibly contribute to this greater risk of relapse.

Source: Mira JA, et al. Frequency of visceral leishmaniasis relapses in Human Immunodeficiency Virus-infected patients receiving Highly Active Antiretroviral Therapy. Am J Trop Med Hyg. 2004;70:298-301.

Thirty-one hiv-infected patients in southern Spain who received HAART after developing visceral leishmaniasis (VL) were included in this retrospective cohort study. Ten patients received secondary prophylaxis for VL, whereas 21 patients did not receive any prophylaxis. Four patients were lost to follow-up, and 10 died. Two deaths were due to symptomatic VL relapse.

Of the 21 HIV patients receiving HAART who were not treated with VL prophylaxis, 8 patients (38%) had a VL relapse. Five of these 8 patients were active intravenous drug users at the time their VL relapse was diagnosed. All patients who relapsed had a CD4+ cell count less than 200 cells/mm3, with a median CD4+ cell count of 33 cells/mm3 at the end of follow-up. None of the patients with relapses showed an increase of more than 100 CD4+ cells/mm3 over their baseline. In contrast, patients who did not receive VL prophylaxis, but did not relapse either, had a median CD4+ count of 188 cells/mm3 at the end of follow-up, and significantly lower HIV-RNA viral loads.

In the group of 10 patients that received secondary VL prophylaxis, only 1 patient relapsed after beginning HAART. This intravenous drug user had 4 relapses of symptomatic VL before starting HAART and 3 subsequent relapses after HAART began, despite directly observed therapy of his antiretroviral medications.

Comment by Mary-Louise Scully, MD

Visceral leishmaniasis is the fourth most frequent opportunistic infection associated with acquired immuno-deficiency syndrome in Southern Spain. A recent study documented a 64.8% decrease in incidence of VL since the standard use of HAART in 1997.1 In addition, it has been shown that HAART prevents the development of overt kala-azar in patients with subclinical VL.2 Therefore, the use of HAART has had a clear impact on the incidence and progression of symptomatic VL.

This study set out to clarify the effect of HAART on relapses of VL in HIV patients. An earlier report, albeit on a small number of patients, showed VL relapses occurred despite patients having an undetectable HIV viral load.3 These findings were in contrast to others in which VL relapse was more common in HIV patients who had a poor recovery of CD4+ counts.4

The present study examined relapse rates both in patients that had secondary prophylaxis for VL and those who did not. Only 1 patient among the 10 patients who had prophylaxis relapsed. This patient was unusual in having 4VL relapses before, and 3 relapses after, HAART was initiated, despite directly observed therapy and undetectable HIV viral load. The fact that this patient was an active drug user raises the possibility of reinfection rather than relapse, as it is known that Leishmania infantum infection can be spread among intravenous drug users.5 This 1 patient also demonstrates that relapses or reinfections of VL can occur despite secondary VL prophylaxis.

Of the patients with VL relapse not receiving prophylaxis, relapse was seen in those patients with less than a 100 CD4+ cell increase over baseline and higher levels of HIV viral RNA at their last visit. These results confirm that relapses of VL are more likely to occur in patients showing poor control of viral replication and poor immunologic responses. Although not statistically significant, there was evidence that failure of immune reconstitution was in part due to low adherence to HAART in this drug user cohort. None of the patients who had CD4+ cell counts over 200 cells/mm3 relapsed, indicating that this may be a safe level at which prophylaxis for VL can be discontinued. Presently, most physicians wait until the CD4+ count is greater than 350 cells/mm3 before discontinuation of prophylaxis. Prophylaxis regimens vary, but some options include pentavalent antimony or pentamidine given monthly, liposomal amphotericin B every 2 weeks, allopurinol, or itraconazole. Comparative studies are few, but 1 study showed pentavalent antimony, given monthly, prevented relapse in 93% of patients during the first year, as opposed to only 23% relapse prevention in those given allopurinol alone.6

As the incidence of symptomatic VL decreases in the era of HAART, it will be increasingly difficult to find enough patients to further study risk factors for VL relapses. Although conflicting data have appeared in previous literature, the take-home message is this: relapses of VL in HIV patients receiving HAART are primarily seen in patients with poor immune reconstitution and uncontrolled viral replication. In such patients, the best approach to prevention of VL relapse would be encouraging patient compliance to HAART and continuation of secondary prophylaxis until appropriate CD4+ counts are achieved.

References

1. de la Rosa, et al. Incidence of and risk factors for symptomatic visceral leishmaniasis among human immunodeficiency virus type 1-infected patients from Spain in the era of highly active anti-retroviral therapy. J Clin Microbiol.2002;40:762-767.

2. de la Rosa, et al. Influence of highly active antiretroviral therapy on the outcome of subclinical visceral leishmaniasis in HIV-infected patients. Clin Infect Dis. 2001;32:633-635.

3. Villanueva JL. Prospective evaluation and follow-up of European patients with visceral leishmaniasis and HIV-1 coinfection in the era of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis. 2000; 19:798-801.

4. Casado JL. Relapsing visceral leishmaniasis in HIV-infected patients undergoing successful protease inhibitor therapy. Eur J Clin Microbiol Infect Dis. 2001;20:202-205.

5. Pineda JA, et al. Evidence of increased risk for Leishmania infantum infection among HIV-seronegative intravenous drug users from Southern Spain. Eur J Clin Microbiol Infect Dis. 2001;20: 354-357.

6. Ribera E, et al. Prophylaxis of visceral leishmaniasis in human immunodeficiency virus infected patients. Am J Med. 1996;100:496-501.

Mary-Louise Scully, MD, Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, California, is Associate Editor of Travel Medicine Advisor.