Updates By Carol A. Kemper
Updates
By Carol A. Kemper, MD, FACP, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, Section Editor, Updates; Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Which do You Treat First — HCV or HIV?
Source: Labarga P, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-Infected patients. J Infect Dis. 2007;196:670-676.
Reduction of treatment-related toxicities have direct bearing on the decision when to initiate antiretroviral therapy. Clinicians may opt to delay antiretroviral therapy or avoid certain agents because of quality-of-life issues and the risk of treatment-related toxicity. Fears of hepatotoxicity may drive decisions regarding treatment, especially in patients with higher CD4 counts (eg, with the use of nevirapine) or in patients with chronic HCV.
Labarga et al determined the risk of antiretroviral treatment-related toxicity in 132 patients with HCV/HIV co-infection, who had received a full course of interferon therapy. Most patients had early HIV disease (the mean CD4 for the group was > 600), allowing for a reasonable delay in HIV treatment. A sustained HCV virologic response (SVR) was achieved in 33%. Despite treatment with interferon, 40% had advanced liver fibrosis (using a composite endpoint of liver disease). Following completion of interferon therapy and initiation of HAART, liver toxicity events were recorded, including symptomatic elevations in liver enzymes, all grade 3 and 4 elevations in transaminases (> 5-fold the upper limit of normal or > 3.5-fold baseline values, if already elevated), and events resulting in discontinuation of drug or a change in the regimen. A total of 49 episodes of liver toxicity occurred during a mean follow-up of 35 months (~9.7% per year). The majority of these episodes were attributed to either dideoxynucleoside analogues (i.e. didanosine and stavudine) (40%) or nevirapine (30%), while liver toxicity from efavirenz (11%) and protease inhibitors (8%) was less frequent. About one-fourth of patients had symptomatic elevations in liver enzymes that did not achieve grade 3 or 4, and about 4% resulted in discontinuation of drug or a change in the regimen.
Liver toxicity was significantly less frequent in patients who achieved a SVR compared with those who did not (3.1% vs 12% per year, p < .001). The proportion having a grade 3 or 4 elevation in ALT was significantly lower in patients achieving SVR than those who did not (6.9% vs 27.3%, p = .007). Hepatotoxic events occurred in 23% and 54% of those without and with advanced liver disease (7.6% vs 11.6% per year, p = .003), respectively.
Logistic regression analysis showed that the lack of SVR and the use of dideoxynucleosides were the only predictors of liver toxicity.
For patients in the developed world, these findings may not be that relevant, as the use of dideoxynucleosides has all but vanished. Patients in the developing world are, however, still receiving these agents, and for these patients, these data may be helpful in recognizing the risk of treatment in patients with HIV/HCV. Such patients seldom have access to interferon therapy for HCV.
For patients in the developed world, the question remains whether to reasonably delay initiation of HAART in those who could first be treated for HCV. For those asymptomatic patients with higher CD4 counts, this may be reasonable. However, since most hepatotoxicity can be managed with little long-term sequela, and most events are not life-threatening (and only 4% resulted in a change in therapy), the presence of HCV should not dissuade physicians from initiation of ART as soon as is reasonable.
Toxoplasmosis in Marine Animals
Source: Massie G, et al. 108th American Society of Microbiology General Meeting, June 6, 2008.
Toxoplasmosis is generally understood to be a disease of meat-eaters. T. gondii has a predilection for muscle and brain, where it encysts — waiting to be eaten by the next carnivore. Most humans acquire toxoplasmosis from undercooked meat, although garden produce contaminated with cat feces may also be a significant source of infection. Cases of acute toxoplasmosis, in my practice, have included a middle-aged woman on an eco-tour of Costa Rico, where she ate deer cooked over an open barbecue, and one patient who dined on elk tartar. Lately, I cannot but wonder about the homemade venison sausage we get from home every Christmas, previously considered a real treat.
But how did the otters off the coast of California become such frequent victims of toxoplasmosis? They don't exactly eat elk. While it is conceivable cat feces have contaminated local water run-off into the ocean, the worldwide spread of toxoplasmosis in marine life seems too extensive for this explanation. Although sea otters off the California coast have been hard hit (17% of sea otter deaths are currently being attributed to toxoplasmosis), toxoplasmosis has now been reported in beluga whales, dolphins, sea lions, and seals, extending from one end of the globe to the other.
A graduate student at CalPoly may have an answer: according to a preliminary paper presented at ASM this year, northern sea anchovies, which are considered "filter feeders", are able to filter T. gondii oocysts. Anchovies are a favorite food of sea otters. If anchovies prove to harbor infectious oocysts, it could explain the spread of toxoplasmosis to marine mammals.
Response to Therapy for Strongyloides
Source: Boscolo M, et al. Evaluation of an indirect immunofluorescence assay for Strongyloidiasis as a tool for diagnosis and follow-up. Clin Vaccine Immunol. 2007;14:129-133.
Sometimes patients ask the greatest questions. A middle-aged woman, who had traveled extensively as a younger woman, presented with a two-year pruritic rash. Her husband has occasional respiratory symptoms, and her 24-year-old daughter (who had been dragged along on the family sojourns to 21 different countries) had occasional pruritus and abdominal pain. My patient had been to several dermatologists, biopsies were non-specific, and topical steroidal creams were of no benefit. Serologies for strongyloides stercoralis were positive in three of four family members — only a younger sibling who had missed all of the fun was seronegative. Antibody tests for Schistosoma were negative, and multiple stool specimens in each were negative. All three received ivermectin 200 m/kg daily for two days, and again two weeks later.
Since the goal of therapy is a cure, how does one assess response to therapy, other than possibly based on a symptomatic response? Serological testing for strongyloides may have varying degrees of sensitivity, the cut-offs are not well-defined, and they frequently cross-react with other helminthes. One smaller study found that antibody levels declined in only one of eight patients following treatment.
Boscolo et al followed changes in S. stercoralis antibody titers in a group of 155 patients at ~4 months post-treatment. Symptoms were common (84%), and included pruritus (59%), abdominal pain (48%), skin rash (25%), respiratory symptoms (14%), and diarrhea (10%). Patients received either thiabendazole or a single dose of ivermectin 200 m/kg. Antibodies were measured using an indirect immunofluorescence antibody test (IFAT) for S. stercoralis, which has the advantage of providing a quantitative result of the specific antibody titer. Based on assessment of patients with confirmed stool diagnosis of S. stercoralis vs those admitted to Italian hospital for other reasons, the sensitivity and specificity of the assay was determined to be 97% and 98%, respectively.
Four months following treatment, 60% had an apparent response to treatment, based on antibody response, with either seroreversion (36%) or a decrease in antibody titer (24%). Seventeen percent had only a one-fold reduction in antibody titer, while 23% had a stable or increased antibody titer. Patients with higher antibody titers were more likely to respond to therapy.
A second study from the Queensland Institute for Medical Research assessed antibody titers before and after treatment in a group of 79 seropositive Aboriginals living in an area of Northern Australia endemic for strongyloides.1 During the initial study period, patients received albendazole 400 mg daily for 3 days as directly observed therapy in the clinic; if they remained seropositive, therapy was repeated. Once ivermectin was available for use in 2000, seropositive patients received a single dose of ivermectin 200 m/kg. Most patients received multiple courses of therapy with either or both agents, although 19 received a single dose of ivermectin. Four patients failed to return to clinic to complete their DOT therapy (three received a single dose of albendazole and one received several single-day courses of albenazole). Antibody was measured using an IgG ELISA test at least three months following treatment; the median interval between the pre-treatment and follow-up antibody tests was about one year.
Seroreversion occurred in 68% of patients receiving a single dose of iver-mectin, and 83% of patients receiving multiple course of ivermectin eventually experienced seroreversion. A three-day course of albendazole resulted in 40% response antibody response, whereas none of five patients receiving a single dose of albendazole serore-verted. Overall, seroresponses were observed in 70% of patients received one or more three-day courses of albendazole.
Despite repeated courses of therapy, 22% remained seropositive. In contrast to Boscolo et al, poorer seroresponses were observed in patients with higher antibody titers, although titers in a few patients were more suggestive of re-infection than failure. Whether the presence of persistent antibody in the remaining patients indicates treatment failure or a serofast state, is not clear. However, the observation of seroresponse in those receiving repeated courses of therapy suggests that antibody levels can be used to assess response to therapy.
References
- Page WA, et al. Utility of serological follow-up of chronic strongyloidiasis after anthelminthic chemotherapy. Trans R Soc Trop Med Hyg. 2006;100:1056-1062.
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