Impact of HAART on Opportunistic Infections (ICAAC)
As NATAP reported in our July newsletter issue of NATAP Reports, there were numerous reports at the ‘97 Human Antiretroviruses Conference showing that some individuals experienced remission of opportunistic infections after initiation of potent antiretroviral therapy. A general decline in the overall incidence of the development of Ois due to potent therapy was reported. Additionally, it has been reported that a reduction in viral load correlates with the development of Ois. In fact, a reduction in viral load as small as 0.5 log can be adequate to reduce the incidence of Ois. Several research efforts have shown that HAART can induce a partial immune restoration for some individuals. Two studies have shown initial increases in memory CD4 cells followed by increases in naive CD4 cells after the initiation of HAART. Additional research is planned to confirm these positive results and to better understand the mechanisms of action. Of course, the longer term effects of protease inhibitors and NNRTIs have to be continually followed for safety, side effects, toxicities and clinical benefit. The follow-up of CD4 increases and viral load declines with individuals taking protease inhibitors is limited to 2 years.
Decreasing Incidence of Oropharyngeal Candidiasis after
Introduction of Protease Inhibitors (abstract I-28).
This was a report of a combined retrospective look at case studies and patient interview
surveys during three months prior to and immediately after starting combination
antiretroviral therapy including a protease inhibitor. Inestigators compared the number of
incidences of OPC in 3 months preceding therapy and 3 months following initiation of
therapy using Wilicoxon signed rank test.
There was a modest but significant increase in the median CD4 count from 60 to 130 cells. There was a high statistically significant reduction in the incidence of episodes of OPC in all patients from 1.43 episodes/month to 0.27 episodes/month after initiation of treatment. In the 35 patients who had previously experienced an OPC episode prior to protease inhibitor therapy, there was a reduction from the mean 2.15 episodes/month to 0.39 episodes/month.
Decreased Incidence of Disseminated MAC in 689 Patients Receiving Protease Inhibitors (abstract I-30). Investigators concluded HAART, inducing both a decrease in viral load and an increase in CD4, has led to a dramatic 10-fold decrease in disseminated MAC incidence from 15% to 1.8%. This report came from investigators at the Hopital de la Pitie-Salpetriere in Paris, France. They reported that DMAC incidence was not significantly different in the first semester of 1995 to the first semester 1996. Following the introduction of protease inhibitor therapy in June ‘96 they saw a dramatic reduction in DMAC in second semester ‘96 compared to second semester ‘95.
In 689 patients receiving HAART regimen containing a protease inhibitor, only 7 cases (1%) of MAC infections occurred. The median interval between beginning HAART and MAC diagnosis was 60 days (range (10-90). In all but one person, the CD4 count was <50 (median 14) and the viral load was >50,000 copies/ml (median 98,000). One person had a viral load <200 copies/ml but a low CD4 of 76.
Impact of HAART on CMV (abstract I-31).
Investigators from Hopital de la Pitie-Salpetriere saw a significant reduction in the
incidence of CMV from 18.7 first episodes per 100 person-years (during January ‘95
through June ‘96) to 5.0 episodes per 100 person-years (for July through
December’96), from a prospective cohort of over 2,000 individuals assembled in 1981.
Despite HAART, 14 patients had their first episode of CMV disease (7 retinitis, 1 pulmonary localization, 1 peripheral nervous system localization, 5 gastr-intestinal involvement). For these patients, the median CD4 count was <20 and only 2 had CD4 >100. The investigators concluded that immune restoration induced by HAART decreased the incidence of CMV. Whether the quality of the immune restoration will allow for discontinuation of chronic maintenance therapy for CMV retinitis requires further investigation. The ACTG is planning studies to explore this question.
Remission of AIDS Associated Microsporidiosis with
combination Protease Inhibitor Therapy (abstract I-32).
Investigators from Hopitaux de Paris in France reported they retrospectively reviewed the
records of 15 men with intestinal microsporidiosis due to E.bieneusi infection. All
patients had chronic diarrhea and persistent shedding of microsporidial spores in stools.
Diagnosis with E.bieneusi was confirmed by electron microscopy analysis of duodenal
biopsies.
In 1996, all patients started a potent antiretroviral regimen of ritonavir or indinavir with 2 nucleosides. The median baseline CD4 and CD8 were 25 and 373, respectively. The mean body weight was 61 kg. Subsequent stool examinations were performed and microsporial spores were cleared from all patients with a median of 3.5 months (range1 to 8 mos). Mean weight gain was 2 kg. Further follow-up to April ‘97 has confirmed remission of intestinal microsporidiosis as stools remained persistently negative for microspoidial spores with a median follow-up of 6 months (range 4 to 10 mos). Diarrhea was resolved in all patients. However, it is possible that a low degree of tissue infection may persist since follow-up intestinal biopsies were not performed.
Lack of Progression after Discontinuation of Maintenance
Therapy for CMV Retinitis I Patients responding to HAART (I-33).
30 subjects at UCSD identified as having healed CMV Retinitis and rises in CD4 count were
discontinued from their CMV maintenance therapy after being on HAART for an average of 398
days (range 331 to 437). Eight patients discontinued maintenance (from 11/95 to 2/97)
therapy after long periods of non-progression. CMV retinitis had been diagnosed for 1.8
years and required 1 to 4 inductions. Five were receiving oral or intravenous ganciclovir,
and 3 were receiving ad hoc cidofover intravenous injections. Wide angle fungus
photographs were obtained every 2 weeks after discontinuation. Time to progression was
assessed by an opthamologist blinded to the treatment. CD4s and viral load were obtained
from individual charts.
At the time of discontinuation (398 days after start of HAART), median CD4 increased to 172 (range 63-404)and viral load was 68,000 copies/ml (range <200 to 508,000). As of May 1997, despite 6/8 patients having detectable viral load (40,000; range 409-423,000), no patient has progressed after a follow up of 146 days (range 72-205 ), and CD4 remain elevated at 198 (44-507). Investigators suggested that HAART restores CMV specific immunity even in patients without complete suppression of viral load. The ACTG is planning studies to explore discontinuation of CMV maintenance therapy.
Two additional research groups reported abstracts of their observations on individuals taking protease inhibitor therapy and the development of CMV. A group in Madrid (abstract I-36)reported a 50% relapse rate after initiation of HAART for a group of 17 individuals who had stable CMV retinitis despite increases in CD4s and decreases in viral load for individuals who relapsed. A French group (abstract I-37) reported data suggesting that for individuals at high risk for CMV disease, protease inhibitor therapy decreases the risk of CMV disease and CMV dissemination in blood. However, CMV viremia can still occur in individuals who had negative blood cultures before protease inhibitor therapy. CMV viremia does not appear as highly predictive of CMV disease in patients receiving protease inhibitor therapy.
HAART Significantly Improves Prognosis of Patients with
HIV-associated Progressive Multifocal Leukencephalopathy (PML). (abstract I-34).
PML affects up to 8% of patients with AIDS and has a dismal prognosis with a median
survival of less than 6 months. Existing treatment options have not been effective. A
retrospective analysis was conducted for 29 patients (25 men) with histologically or PCR
confirmed PML. The mean age was 39 years. Median CD4 count was 40 and 6 patients had CD4s
>200. Fourteen patients never received or stopped therapy following diagnosis (group
A), 10 were treated with nucleosides alone (group B), and 5 were started with HAART
including a protease inhibitor (group C).
Median survival for the groups were - 123 days for group A and 127 days for group B. Clearly, the superior response was >403 days for group C. Four out of 5 patients taking HAART are still alive and progressing less rapidly or have experienced some improvement of their symptoms.
Decrease of Intestinal Cryptosporidiosis Concomitant to Use of Protease Inhibitors (abstract I-38). A group of investigators from France reported a decrease in the incidence of reported cases of patients with stool specimens positive for Cryptosporidium parvum from January ‘95 to December ‘96 in 10 participating centers. The number of postive stools declined from a median of 23/month in May ‘96 to 19/mo in June ‘96, 14/mo in July ‘96, and stabilized at 8/mo from August to December ‘96. This reduced prevalence occurred as protease inhibitors began being prescribed in France at the end of March ‘96. In the last term of 1996, about 56% of patients with <200 CD4 were receiving protease inhibitor therapy.