Notes and Quotes

Glutamine-based supplements improve diarrhoea and levels of antiretroviral drugs Oral supplements of glutamine or alanyl-glutamine alleviate persistent diarrhoea and boost the levels of antiretroviral (ARV) drugs in the blood, according to a pilot study conducted in northeast Brazil. [Clin Infect Dis 2004, 38:1764–1770.] Glutamine, an amino acid, plays a key role in preserving the structure and function of the mucosal lining of the intestines. Although available as a white powder at health food stores, glutamine is poorly soluble and is thought to morph into glutamate, an essential but potentially toxic amino acid, once it contacts the acidic juices in the stomach. However, its dipeptide derivative, alanyl-glutamine, dissolves 20 times more easily, remains stable, and is well tolerated. Animal and tissue culture studies have shown that both compounds speed healing of intestinal villi and drive sodium absorption. Richard Guerrant of the University of Virginia, Charlottesville, and colleagues in the USA and Brazil speculated that oral doses of the compounds might increase the absorption of ARV drugs in AIDS patients, as well. (Members of the research team have previously reported that some ARV drugs are poorly absorbed in patients with chronic diarrhoea and wasting.) For the randomized, double-blinded placebo- controlled study, the researchers recruited 12 women and 39 men infected with HIV who came to the Hospital Sao Jose in Ceará, Brazil, to be treated for diarrhoea and wasting. The participants were divided into four groups: 11 patients received a daily dose of 30 g glutamine and 15 g glycine; 11 received 4 g of alanyl-glutamine plus 42 g glycine once a day; and 10 took 44 g of alanyl-glutamine each day. The nine patients in the control group received a daily supplement of 46 g glycine, an amino acid that has no effect on diarrhoea. The solutions were designed to contain equal amounts of nitrogen, a key ingredient for intestinal repair. The 9-day study consisted of 2 initial days of observed ARV drug therapy followed by 7 days of ARV drug therapy combined with the oral supplements. Each day the patients were asked about the frequency and consistency of their diarrhoea as well as other gastrointestinal complaints. Blood and urine samples were taken on days 3 and 9. The researchers were encouraged by the results. Diarrhoea symptoms lessened in 26 of the 30 patients who had taken any of the three glutamine-based supplements. Their urine samples contained more mannitol by the end of the week as well, indicating that the absorptive lining of the intestines was being rebuilt. Additionally, all three glutamine-based supplements significantly raised the amount of nucleoside reverse-transcriptase inhibitors (NRTI) measured in the blood 2 h after dosing. The biggest boost came with high-dose alanyl-glutamine: NRTI levels jumped an average of 113% for the high-dose patients compared with 14% and 8%, respectively, for the glutamine and low-dose alanyl-glutamine groups. When assessed as the percentage of patients, 9 out of 12 (75%) of the paired 2-h drug levels were higher in patients on high-dose alanyl-glutamine compared to 11 out of 20 (55%) patients receiving the low-dose solution, and 9 out of 14 (64.3%) patients taking glutamine. According to Guerrant, who has patented the use of alanyl-glutamine for oral rehydration and nutrition therapy, the findings suggest that in the future ‘‘getting antiretroviral therapy to effectively treat the patients who need it most, may involve not only the drugs but improving the patient's ability to absorb those drugs.’' Controlling diarrhoea may also help curb the emergence of drug-resistant HIV. In the Brazil study, the researchers found a high frequency of HIV mutations resistant to ARV drugs that were malabsorbed by the patients. HIV genotyping for 9 out of 16 participants showed 65 resistance mutations of which 45 (69.2%) were resistant to ARV drugs that the patients had in their blood at below optimal levels. ‘‘We don't have a significant correlation yet of drug malabsorption as something that actually drives resistant virus,’’ says Guerrant. ‘‘But we're attempting to get a handle on it in studies with colleagues in Haiti.’’ In Brazil, more than 60% of all patients with HIV initially visit a doctor to be treated for diarrhoea, a figure comparable to that in other developing countries. Accepted 7 July 2004 Protease inhibitors and risk of developing HIV-related sensory neuropathy Several protease inhibitors are associated with an increased risk of developing HIV-related sensory neuropathy, according to Calgary, Alberta-based researchers reporting at the 56th Annual Meeting of the American Academy of Neurology in San Francisco last April. Although peripheral neuropathy has been linked to antiretroviral drugs, namely nucleoside reverse transcriptase inhibitors (NRTI), the current study is the first to find an association with protease inhibitors. Sensory neuropathies are increasingly common among individuals with advanced HIV infection—about one in three develops some form of neuropathy. The most common disorder, distal sensory polyneuropathy, causes pain and numbness in the feet or, less frequently, the hands. Severe cases can lead to autonomic dysfunction and gait difficulty. Antiretroviral toxic neuropathy, another HIV-related neuropathy, causes similar symptoms but develops 3–6 months after patients begin using certain NRTI, including didanosine, zalcitabine, and stavudine. To explore the various risk factors for developing an HIV-related sensory neuropathy, a team of researchers led by University of Calgary neurologist Christopher Power studied 221 HIV-positive individuals with various neurological diseases. Among the patients, 29% had distal sensory polyneuropathy and 17% had antiretroviral toxic neuropathy. By comparing those individuals with the patients who did not have a sensory neuropathy, the researchers determined that older age, diabetes, peak viral load, poor quality of life and use of didanosine, zalcitabine and stavudine were specific risk factors for neuropathy. But it came as ‘‘a big surprise’', Power says, when the analysis also showed an association with three protease inhibitors: indinavir, saquinavir and ritonavir. Patients with neuropathy were getting higher exposure times and cumulative dosages of those three protease inhibitors. Conversely, the researchers found no link between nelfinavir, lopinavir or amprenavir, three other protease inhibitors, and neuropathy. Power says that while the study is preliminary, ‘‘it raises the unpleasant specter that protease inhibitors might also have an adverse effect on neuropathy.’’ Just how protease inhibitors may cause neuropathy remains unclear. Power suggests that the mechanism might lie in drug-induced metabolic abnormalities like those seen in lipid and glucose metabolism with antiretrovirals. Accepted 28 July 2004 Cervical cancer risk for HIV-infected women smokers HIV-infected women who smoke may have a particularly high risk for cervical cancer, say researchers who found a significantly higher prevalence and incidence of human papillomavirus (HPV) infections among such women (J Infect Dis 2004, 189:1821–1828). ‘‘It's one more piece in a elegant public health message about the risks of smoking,’’ says lead author Howard Minkoff of the Maimonides Medical Center in Brooklyn, New York. HPV infection is associated with almost all cervical cancers. Several studies suggest that smoking plays a role in HPV-related cervical disease, possibly by hampering the body's immune response to the virus. Still other studies, including some by Minkoff, have shown a higher frequency of HPV infections and related lesions among HIV-infected women. To see if smoking worsens HPV infections in co-infected women, Minkoff and his colleagues reviewed the medical data of 1797 HIV-infected women and 496 HIV-negative women enrolled in the Women's Interagency HIV Study from October 1994 to January 1998. Every 6 months, the participants had a medical examination that, for their first five visits, included a cervicovaginal lavage for HPV DNA testing. They were also asked about their smoking status at each visit. Various analyses of the data showed that smoking does indeed aggravate HPV infection ‘‘no matter how you cut the cake,’’ Minkoff says. At baseline, for example, the prevalence of high-risk HPV was 28.4% in women who reported smoking compared to 25% in women who did not. Similarly, the prevalence of low-risk HPV types was 6.4% in smokers compared to 5.6% in nonsmokers. HIV-infected women were 3.9 times more likely to have a prevalent HPV infection. The occurrence of HPV types that were not initially present but appeared at subsequent visits was also linked to smoking among HIV-infected women. Overall, HIV-infected women were 3.13-fold more likely to have an incident HPV infection than HIV-negative women. The researchers also found that, compared to HIV-uninfected women and nonsmokers, HIV-infected women and smokers were significantly more likely to have the same type of HPV detected during at least two consecutive visits. Persistent HPV infections are considered a high risk for developing cervical cancer. The likelihood of acquiring a persistent HPV is greater for women who smoke, the researchers explain, because smokers tend to get more HPV infections. Charlene Crabb

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