8th Annual Retrovirus Conference
OPPORTUNISTIC INFECTIONS & NEUROLOGIC CONDITIONS
Section by David Alain Wohl, MD with selected reports by Harvey S. Bartnof, MD and Jules Levin
The number of presentations about opportunistic infections (OIs) continues to remain low in developed countries, due to the benefits of HAART. In the resource-rich nations, OIs occur mostly among those who are not taking HAART or for whom HAART has "failed." It is no coincidence that the Conference organizers informed the Press that the official "abbreviated title" of the Conference is now the "8th Annual Retrovirus Conference," leaving out the "Opportunistic Infections" part.
Rachael Schrier, MD of the University of California, San Diego reported that patients with "immune recovery uveitis" eye inflammation after CMV (cytomegalovirus) retinitis is treated and HAART was started tended to have had a shorter course of anti-CMV maintenance therapy following diagnosis of retinitis and higher levels of IL-12 in their eyes than patients with active retinitis (abstract 31). Also, among those with uveitis, "systemic T-cell lymphoproliferative responses" to CMV were greater than the responses observed in patients without uveitis. Untreated CMV without HAART is a common cause of blindness in AIDS patients.
Dr. M. F. Para of Ohio State University reported that AIDS patients with CMV viremia (in the blood) were more than 5 times more likely to develop CMV disease (retinitis eye infection, colitis intestinal infection) than those who did not have viremia (relative hazard 5.6). Also, CMV viremia was associated with a decreased "Karnofsky performance" score, indicating a negative effect on daily functioning (abstract 555). Interestingly, there was an average 90-day delay in the decline of blood CMV after starting HAART. Among the 511 patients in the Viral Activation Transfusion Study, the median CD4 cell count was 15 cells per microliter.
C. Mussini, MD of Modena, Italy has reported that "maintenance" therapy for AIDS patients who have had "cryptococcal meningitis" (fungal infection of brain coverings) can be stopped safely among those who respond to HAART (abstract 546). A total of 24 discontinued their anti-fungal medication after a median 25 months from the diagnosis of meningitis and 2 years of HAART, while another 22 continued cryptococcal maintenance therapy. The mean CD4 cell count at the time of anti-fungal cessation was 80 cells per microliter with an average HIV viral load of 2.6 log (254) copies per milliliter. The results showed that no episodes of recurrent cryptococcal meningitis occurred in either group during the observation period. This small, observational, non-randomized study suggests that cryptococcus could be added to the list of OIs for which response to HAART confers protection. Previously, the safety of discontinuing CMV maintenance therapy and prophylaxis for "PCP" (Pneumocystis pneumonia, lung infection) and "MAC" (Mycobacterium avium blood infection) have been demonstrated in several published papers of patients who have a sustained response to HAART.
The combination of HAART and radiation was found to be associated with a 6-fold greater chance of survival in patients with primary central nervous system lymphoma (PCNSL, brain cancer), according to Dr. C. Hoffmann of Munich, Germany (abstract 590). In a "multivariate" statistical analysis of 29 patients with biopsy proven PCNSL, those treated with both therapies lived a median of 1,093 days, compared to 132 days among those treated only with radiation, and 33 days for those who received neither. Fortunately, the incidence of PCNSL has decreased markedly in the era of HAART.
Other reports included:
"PML" (progressive multifocal leukoencephalopathy, brain infection with "JC" virus) may manifest as an "immune recovery illness," according to Dr. P. Miralles of Hospital Gregoria Maranon in Madrid, Spain (abstract 598). Immune recovery illnesses occur when the immune system responds to HAART and causes symptoms of infection that was present previously without symptoms. Examples include tuberculosis, herpes zoster ("shingles") and CMV immune vitritis (uveitis, discussed above).
27% of 11 patients with PML (see above) responded to a 21-day infusion of topotecan (Hycamtin, anti-cancer drug), according to Dr. B. Dupont of the Pasteur Institute in Paris, France (abstract 597). Topotecan has anti-JC virus and anti-HIV effects.
HAART significantly prolonged survival in AIDS patients with NHL (non-Hodgkins lymphoma, cancer), according to Dr. H. Tam of the University of California at Los Angeles (abstract 589). A multivariate analysis was used to determine that the "relative hazard" for death was 0.19 among patients with NHL who took HAART either prior to or after the diagnosis. NHL is still a common cancer in the era of HAART--some studies have shown that the incidence rate of this "opportunistic cancer" has not decreased in the HAART era. In similar analyses, Dr. Tam also showed that HAART had significantly improved survival in those with AIDS-related Kaposis sarcoma, a cancer that is much less common in the HAART era.
Justin McArthur, PhD of Johns Hopkins University reviewed the topic of "peripheral neuropathy" (numbness, burning, tingling, pain in feet), a condition that still occurs among patients with HIV infection. Causes of this condition include: high HIV RNA levels; low CD4 count; the "d" drugs in the NRTI drug class to treat HIV (ddI, d4T, and ddC); AIDS wasting syndrome (weight loss without infection or dieting); dapsone antibiotic; alcohol; increased age; and diabetes. Those with HIV RNA levels greater than 10,000 copies per milliliter have a much higher risk (about 25% over 10 years) of being diagnosed with peripheral neuropathy compared to those with lower viral loads. Combining 2 of those NRTI "d" drugs increases the risk, particularly if used with hydroxyurea (Hydrea, Droxia, anti-cancer and anti-sickle cell anemia drug).
In series of impressive photographs, Dr. McArthur showed that the number of nerve fibers in skin biopsies of the leg was reduced in patients with peripheral neuropathy compared to controls. The pictures support the hypothesis that blood "macrophages" (immune cells) that are activated during HIV infection produce substances that lead to inflammation and a reduction of the small nerves. It is theorized that "mitochondrial" (energy-producing component of cells) toxicity might be the cause. However, this has yet to be demonstrated. This experimental "punch" skin biopsy procedure may be helpful in following the development of peripheral neuropathy and evaluating whether an HIV medication was increasing it. To read more about that topic, go the Internet website http://www.natap.org/2001/feb/retroconf/neuropathy020701.htm.
In a presentation by Dr. Bruce Brew of Sydney, Australia, peripheral neuropathy was strongly associated with having an elevated venous (vein) blood lactate level in 73 patients (abstract 9). The results showed that 90% of the 20 patients with d4T-related peripheral neuropathy had elevated lactate levels (mean lactate 3.16 millimoles per liter) compared to 15% of the 20 patients taking d4T without neuropathy (mean lactate 1.68) and 10% of the 10 patients with HIV-related neuropathy (mean lactate 1.8). Both "lactic acidosis" (life threatening high acid levels with symptoms) and neuropathy are seen more often in patients taking d4T and ddI. This further supports the hypothesis that these drugs might cause neuropathy by "mitochondrial damage." Dr. Brew concluded, "These results suggest that an elevated serum lactate is useful in a patient with a neuropathy in whom nucleoside neuropathy is suspected", as therapy can be modified.
Treatments for peripheral neuropathy include: stopping the potentially causative medication(s), acupuncture, oral amitriptyline (Elavil), oral mexiletine (Mexitil heart rhythm drug), lamotrigine (oral Lamictal anticonvulsant); recombinant human nerve growth factor (rhNGF); oral n-acetyl carnitine; open-toe shoes; and bed covers elevation.
Dr. Irene Cergnul of the Community Research Initiative on AIDS in Bronx, New York reported that a topical solution of aspirin 375 mg in diethyl ether applied 3-times daily for 1-2 weeks significantly decreased pain symptoms using a Brief Pain Index Scale (abstract 601). A total of 43 HIV positive patients (45% women) with "DSPN" (distal sensory polyneuropathy) enrolled in the study that was placebo-controlled, randomized, cross-over, and double-blind (medication or "placebo" not known by patient or treating physician). The dropout rate was 28%; however, 2/3 reportedly did so due to pain relief.