September 28-October 1, 1997
Baril and colleagues from Paris reported on the dramatic decrease in CMV disease in France since the beginning of widespread use of highly active combination regimens which include protease inhibitors, and cast some light on the effect of HAART on the risk of disease. (Editorial comment: I don't love the term HAART because it is not clear what is meant. Does it include adding a protease inhibitor to existing therapy? What about less effective agents, such as the old hard gel formulation of saquinavir? In these presentations, it generally meant indinavir or ritonavir with at least one new nuke)
She examined the rate of CMV disease among all patients with AIDS at Hopital Pitie Salpetriere, from the beginning of 1995 until the end of 1996. Indinavir and Ritonavir became available in late March of 1996. The rate of new cases of CMV plummeted in the second half of 1996 from 16-20 cases per 100 AIDS patients to 1 per 100 patients. However, they did diagnose 14 cases of CMV among patients on HAART. Eleven of the 14 cases occurred during the first 8 weeks after starting HAART, even though CD4 counts had risen. All new CMV episodes occurred within 4 months of starting HAART.
This study shows that the increase in CD4 cells seen with HAART provides significant protection against CMV, and other papers presented today showed similar results for oral thrush, disseminated MAC, and cryptosporidia. However, a very important point shown here and in a recent paper by Jacobsen is that opportunistic infections can occur during the first few months on HAART, despite newly improved CD4 counts that are quite high. After several months, OI's become much less common. This suggests that the reconstitution of the immune system lags behind increases in CD4 numbers. Can prophylaxis be stopped after the CD4 count rises? Clearly in the first few months. Can it be stopped after a few months of continued response? The answer is not in yet, but some interesting clues are provided in the next two papers.
Dr. Francesca Torriani from UC San Diego presented a tantalizing paper that raised some questions but did not fully answer them. Between October 1995 and May 1997, 8 patients with CMV retinitis and CD4 increases on protease containing regimens chose to stop their maintenance therapy for CMV.
Typically, all would experience recurrence with in a few weeks. The reasons the patients chose to stop were not consistent, and no specific criteria were followed. These were patients with advanced disease: they had had CMV for a median of 1.8 years and the median CD4 count before HAART was 54 cells. At the time they chose to stop CMV therapy, the median CD4 count was 172 (range 63-404). However, 6 of 8 had detectable viral loads. They were followed closely with full opthamologic exams and photographs every 4 weeks. After an average followup of about 6 months, all 8 remain free of CMV recurrence.
It is important to remember that these patients had been on HAART for about 6 months before stopping and were followed very closely. There are only 8, and the period of followup is still very short, but this is very exciting IF it can be confirmed in larger studies. It is too early to recommend this outside of studies. See the next abstract for additional information and discussion.
Dr. Tural from Barcelona reported a similar experience with 7 patients, although they attempted to be more systematic to try and define who is a candidate for stopping maintenance. They approached patients with CMV retinitis who had been on HAART for at least 3 months who met specific criteria. They had to have CD4 counts that had risen to greater than 150, an undetectable HIV RNA (viral load), and no detectable CMV in the bloodstream by PCR. (CMV PCR of the blood identifies patients with a much higher risk of new CMV or recurrences on maintenance) They identified 7 patients who met these criteria and offered them the choice of stopping maintenance therapy.
Antiviral therapy consisted of D4T, 3TC, plus either ritonavir, indinavir or ritonavir with saquinavir. Most were on IV ganciclovir or foscarnet. All 7 chose to participate in the study and had checkups every week for 3 months, including dilated eye exams and CMV PCR. All continued to have undetectable HIV RNA, and the CD4 count rose to and average of 290. With 9-12 months of followup, none of the 7 have had any CMV recurrence.
This study seems to confirm the Torriani paper, and begins to outline who might be a good candidate: those with at least 3 months on HAART, excellent CD4 and viral load response, and no CMV detectable in the blood. A recent paper by Autran in Nature showed a possible laboratory explanation. CD4 cells from patients with AIDS who began HAART were examined in the test tube for their ability to respond to CMV. After 4 weeks, there was some return of response, and it increased steadily over 9 months.
But a great deal of caution is necessary before we start to stop maintenance therapy for CMV. This is only 7 patients and there is only brief followup. They were followed very closely by their opthamologist. CMV may be different from some other OI's since it is a chronic life long infection, and it may be easier to restore immunologic memory. Still, further studies are justified, and for carefully selected patients with complications from maintenance therapy, it is time to think about the balance of risks.
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