Bulletin of Experimental Treatments for AIDS, No. 28; March, 1996
Mark Bowers, Managing Editor of Treatment Publications at the San Francisco AIDS Foundation.

Two Studies Show Some Infants Can Beat HIV

* 299 children became HIV-antibody negative

* 2 European studies support the notion of natural immunity

Two recently reported European studies lend support the long-debated assertion that there is natural immunity to HIV. In the European Collaborative Study of children born to HIV positive mothers, 299 children became negative for the HIV antibody test. 264 of these children were tested by polymerase chain reaction (PCR) for the presence of virus in the blood. 219 children were tested at least twice. PCR detected HIV in 9 children who subsequently were found to have undetectable levels of virus. These children appear to have seroreverted: they were exposed to HIV, were infected for a short time, then cleared the virus.

In December 1995, French researchers found another 12 children whose initial PCR tests were positive for HIV, and who then apparently cleared the virus before their first birthday. A retrospective study of 188 children born to HIV positive mothers over a 6-year period detected HIV by coculture of cord blood, direct culture or PCR. These tests are used because children naturally acquire antibodies from their mothers whether or not they also are infected with HIV. Five of the 12 children who seroreverted had tested positive by no method of detection other than by PCR.

Researchers are now trying to reach consensus on acceptable criteria for determining if children have been transiently infected with HIV. Individual PCR tests may be associated with false-positive results because of laboratory contamination, but repeated PCR tests results are unlikely to be false. If these children are naturally immune, as they appear to be, the data suggests that such immunity is rare. The seroreversions suggest that there is an immunologic mechanism for controlling and eliminating HIV. If researchers can determine what that mechanism is and how it works, they may be able to duplicate it in others, design an effective vaccine and fill in the blanks in understanding HIV pathogenesis.

Roques T and others. Clearance of HIV infection in 12 perinatally infected children: clinical, virological and immunological data. AIDS 9(12): FF19-F26. December 1995.

Newell ML and others. Detection of virus in vertically exposed HIV-antibody-negative children. The Lancet 347:213-214. January 27, 1996. HIV Suppression:Two Groups Identify

Chemical Messengers that Inhibit HIV

For many years, Jay Levy, MD, at the University of California in San Francisco, has looked for a soluble factor, secreted by CD8 cells, that suppresses HIV replication. The CD8 factor is predicted to be initially present and then decrease in rapid progressors, and to be important in long-term non-progressors. Two groups have recently laid claim to the identity of this soluble factor. Robert Gallo, MD, and colleagues, of the Institute for Human Virology, found that 3 chemical messengers produced by CD8 cells could together inhibit different strains of HIV-1, HIV-2 and simian immunodeficiency virus (SIV) in the test tube. The factors have been named RANTES, MIP-1 alpha and MIP-1 beta. Gallo speculates that this discovery could lead to the development of effective therapeutic approaches to AIDS.

Michael Baier, PhD, and fellow researchers in Germany contend that the elusive factor is the newly isolated interleukin 16 (IL-16). The presence of IL-16 in African green monkeys is credited with controlling SIV and preventing the development of simian AIDS. Both groups now must determine whether production of these chemical messengers is defective in rapid progressors. If so, clinical studies in human subjects will soon follow. Baier M and others. HIV suppression by interleukin-16. Nature 378(6557): 563. December 7, 1995.

Cocchi F and others. Identification of RANTES, MIP-1alpha, and MIP-1beta as the major HIV-suppressive factors produced by CD8+ T-cells. Science 270:1811. December 15, 1995.

HIV Concentration During Acute Infection

The currently accepted model of early infection with HIV holds that the concentration of virus in the plasma increases for a few weeks after initial infection, then begins to decrease when the body develops an HIV-specific immune response. British researchers have challenged this model, suggesting that population dynamics, and not the immune system, accounts for sharp decreases in viral load. They argue that measurable virus decreases because HIV runs out of suitable uninfected cells to infect, not because the body has mounted a partially effective immune response to the infection. In fact, in some individuals, viral load was seen to decrease dramatically despite the absence of any measurable antibody or cytotoxic T-cell responses.

Phillips A. Reduction of HIV concentration during acute infection: independence from a specific immune response. Science 271:497-499. January 26, 1996.

* Predicting Progression to AIDS

Polymerase Chain Reaction Found to Predict Progression

The search for a surrogate marker that reliably predicts HIV disease progression has returned mostly disappointing results. Beta-2 microglobulin, neopterin and HIV p24 antigenemia have all been of limited value. CD4 counts and percentages are commonly accepted, but not entirely correlative with disease progression. The latest of 4 studies that support the use of PCR RNA tests for predicting disease progression was reported in Annals of Internal Medicine in November 1995.

A distinction is drawn between 2 kinds of PCR messenger RNA measurement, in plasma and in peripheral blood mononuclear cells (PBMC). Plasma viral load measures, according to Nobel Prize winner Warner Greene, "probably reflect a dynamic balance between the daily production of nearly 1 billion new virions [virus particles] countered in part by the destruction and physical trapping of these virions in the dendritic cell network of the lymph node or other lymphatic tissues." RNA in PBMCs reflects trafficking in and out of lymph nodes and the effects of other infections. Finding HIV messenger RNA in PBMCs strongly predicts future progression to AIDS. Greene said in summary, "For the HIV infected person, the clinician providing care and the scientist attempting to unravel the mysteries of the HIV virus, the identification of an assay potentially capable of predicting future progression or nonprogression to AIDS is very good news indeed."

Greene W. Predicting progression to AIDS. Annals of Internal Medicine 123(9):727-728. November 1, 1995.

Saksela K and others. HIV-1 messenger RNA in peripheral blood mononuclear cells as an early marker for risk for progression to AIDS. Annals of Internal Medicine 123(9):641-648. November 1, 1995.

Typical Progressors, Rapid Progessors and Nonprogressors

In the January 19, 1996 issue of Science, Barton Haynes, MD, Giuseppe Pantaleo, MD, and Anthony Fauci, MD, reported on current understanding of the genetic, immunologic and virologic factors in HIV infected individuals who do or do not progress to AIDS. From 5% to 10% of all HIV infected individuals are asymptomatic after 7-10 years and their CD4 cell counts are stable (nonprogressors); 10% progress to AIDS within 2-3 years (rapid progressors); the rest will on average progress to AIDS about 10 years after initial infection (typical progressors).

Typical progressors characteristically are infected with HIV strains that are homogeneous, that target monocytes, that do not induce syncytia formation (cell clumping) and that replicate slowly during the clinically latent stage. During progression to AIDS, HIV isolates increase their speed of replication and target T-cells. Rapid progressors tend to have an initial high viral load that does not fall to the same lower levels as seen in typical progressors. There are higher levels of HIV messenger RNA compared with other groups, and some people may be infected with rapidly replicating, virulent strains of HIV. Nonprogressors on average have lower viral loads than either of the other 2 groups, and some may be infected with less pathogenic strains of HIV.

A clear set of research priorities is established in the article summary. The key question to be answered is how a low viral load in nonprogressors relates to the pathogenicity of the HIV strain and to anti-HIV immune responses. The next priority is to determine genetic influences on anti-HIV responses and find ways to rebuild the immune system, including use of bone marrow and thymus transplants. The third goal is to understand the role of protective neutralizing antibodies in nonprogressors. The fourth key question is whether a particular interaction between a strain of HIV and a specific host can explain nonprogression. Fifth, immune responses at the mucosa, the most common portal for HIV entry during sexual transmission, need to be adequately characterized in animal models. Sixth, attenuated virus vaccines need to be explored and understood in both newborn and adult rhesus monkeys. Finally, the role of the newly isolated soluble factors secreted by CD8 cells in nonprogression needs to researched. These 7 research priorities will no doubt constitute a blueprint for future HIV research at the National Institutes of Allergy and Infectious Diseases, where Fauci is responsible for setting research policy.

Haynes B and others. Toward an understanding of the correlates of protective immunity to HIV infection. Science 271:324-328. January 19, 1996.

* HIV Treatments

People of Color Experience Same AZT Side Effects as Whites

There is no significant increase in adverse side effects from AZT (Retrovir) use among African-Americans or Hispanics, according to results of a recent University of California at San Francisco study. The study was based on reports from patients about pain or discomfort while using AZT. These results do not mean that these groups do not experience side effects from the use of AZT, only that these effects are the same as those experienced by whites who use the drug.

Jacobson M and others. Zidovudine side effects as reported by black, Hispanic, and white/non-Hispanic patients with early HIV disease: combined analysis of two multicenter placebo-controlled trials. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 11(1): 45-52. January 1996.

Adefovir Dipivoxil Data Released

A Phase I/II study of adefovir dipivoxil, an oral prodrug from the nucleotide analog family, compared 125 mg per day or 250 mg per day to placebo in 72 volunteers with CD4 counts above 200 cells/mm3. Viral load decreased by 0.5 log at the 125 mg dose, and by 0.4 log at the 250 mg dose. Mean CD4 cell counts increased at 12 weeks by 57 cells/mm3 at the 125 mg dose and by 27 cells/mm3 at the 250 mg dose, compared to a loss of 41 cells/mm3 in the placebo group.

Risk Factors for Neuropathy

A comparative study of 103 people who took either ddI (Videx) or ddC (Hivid) assessed whether other risk factors influence the development of peripheral neuropathy. The group under study had a mean age of 39 years and a median CD4 count of 59 cells/mm3. Of the 51 people taking ddC, 14 developed neuropathy, compared to 7 of 55 taking ddI. No independent risk factors were associated with developing neuropathy from ddI, but a history of nervous system disease, heavy alcohol consumption or low serum cobalamin (vitamin B12) levels distinguished those who were at higher risk of toxic neuropathy from ddC.

Fichtenbaum C and others. Risk factors for dideoxynucleoside-induced toxic neuropathy in patients with the human immunodeficiency virus infection. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 10:169-174. October 1995.

3TC and AZT Combination Synergistic

According to a study of 362 people with CD4 cell counts between 200-500 cells/mm3 and little or no prior experience with antiretrovirals, the combination of 3TC (Epivir) and AZT produces more improvement in CD4 percentages and lower viral load than either drug alone. The double-blind comparative study of 300 mg of 3TC every 12 hours, 200 mg of AZT every 8 hours, 150 mg of 3TC every 12 hours plus AZT, or 300 mg of 3TC every 12 hours plus AZT showed that both combination regimens were superior to either drug taken alone. Lower plasma HIV RNA levels and increased percentage of CD4 cells were maintained through 52 weeks.

Eron J and others. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. New England Journal of Medicine 333(O25):1662-1669. December 21, 1995.

DNCB Shows No Clinical, Viral or Immunological Effect

Two small studies assessed the impact of the application of DNCB (dinitrochlorobenzene, a photographic solvent) on viral load, cytokine expression and HIV disease progression. In the first study, 28 asymptomatic HIV positive volunteers with variable CD4 cell counts and no antiviral treatment in the previous 3 months were randomized to receive topical DNCB or placebo for 6 months. All also received Chinese medicine and acupunture. All those who received DNCB developed evidence of skin delayed-type hypersensitivity (rashes) but no major systemic side effects. CD4 counts increased slightly for both placebo and DNCB treated volunteers; CD8 counts increased more in the placebo group than in the DNCB group. DNCB did not produce a significant difference in clinical or immunologic outcomes.

The second study reviewed 8 HIV-infected volunteers who received weekly DNCB applications and oral Chinese herbs, and 3 who received only oral Chinese herbs. Lymph node biopsies were performed at baseline and at 6 months. CD8 cell losses were similar for both groups. CD4 counts in the DNCB group fell from a mean baseline of 448 to 289 cells/mm3 at 6 months (a net loss of 159); CD4 counts in the untreated group fell from 398 to 277 cells/mm3 (a net loss of 121). Because the DNCB group lost more CD4 cells, their percentage of CD8 cells was higher. DNCB did not affect viral burden, viral replication or cytokine expression.

Cohen O and others. Effects of dinitrochlorobenzene therapy on viral load and cytokine expression in lymphoid tissue of HIV-infected individuals. Infectious Diseases Society of America 33rd Annual Meeting. San Francisco. September 16-18, 1995. Abstract 475.

Loveless M and others. Effect of dinitrochlorobenzene (DNCB) cutaneous sensitization on HIV disease progression. Infectious Diseases Society of America 33rd Annual Meeting. San Francisco. September 16-18, 1995. Abstract 471.

* Opportunistic Infections

NTZ for Cryptosporidiosis

UNIMED Pharmaceuticals announced that a compassionate access program has been established for the experimental drug nitazoxanide (NTZ) for the treatment of cryptosporidiosis (call 1-800-864-6330 for more information). A small clinical study in Mexico evaluated 500 mg of NTZ twice a day in 14 people. At 2 weeks, all 14 were negative for stool cultures of Cryptosporidium. The best dose for the drug is not yet established; a clinical study at Cornell Medical Center in New York City will compare 14 days of treatment with 500, 1000, 1500 or 2000 mg daily in 30 volunteers. Treatment extension of 2 or 4 weeks will be made available to those who do not have a complete response.

James J. NTZ: cryptosporidiosis new treatment. AIDS Treatment News 239:1-2. January 19, 1996.

Cryptosporidiosis and Biliary Disease

In March 1993, a waterborne outbreak of cryptosporidiosis occurred in Milwaukee, WI. Of the more than 400,000 people who were affected by drinking water from the contaminated municipal water supply, a significant number were HIV- infected. Researchers evaluated the signs and symptoms of HIV disease, CD4 cell counts and survival in a group of 82 HIV-infected people whose infection with cryptosporidiosis was documented by finding Cryptosporidium in their stools.

Researchers noted a sharp increase in HIV-infected individuals with cryptosporidiosis. Biliary disease was present in 24 people, of whom only 4 (17%) were still alive after 1 year. Biliary disease in people with AIDS can be caused by both Cryptosporidium and cytomegalovirus (CMV), and affects the tracts that carry bile from the liver through the gallbladder to the intestine. Of the 58 people without biliary disease, 30 (52%) were still alive 1 year after the cryptosporidiosis outbreak. Twenty-one of the people with biliary symptoms had CD4 cell counts less than 50 cells/mm3, compared to 36 of the 57 without symptoms.

Researchers conclude that HIV-infected people with CD4 counts less than 50 cells/mm3 who are exposed to Cryptosporidium are at increased risk for biliary symptoms and for death within 1 year of infection. Researchers further caution that "Public water supplies that meet current federal and state standards for drinking water may still become contaminated with cryptosporidial oocysts and cause large outbreaks, as occurred in Milwaukee."

Vakil N. and others. Biliary cryptosporidiosis in HIV-infected people after the waterborne outbreak of cryptosporidiosis in Milwaukee. New England Journal of Medicine 334:19-23. January 4, 1996.

3TC Suppresses Hepatitis B Virus

In a randomized, double-blind, dose-ranging trial of 3TC in 32 people with chronic hepatitis B, participants received either 25, 100 or 300 mg of drug daily for 12 weeks. The drug was well tolerated, and reduced viral RNA levels as measured by PCR to undetectable levels in 70% of those taking 25 mg doses and in all of those taking the higher doses. Traces of hepatitis B virus could be found again in most people after 3TC was discontinued. Larger studies are being planned.

Dienstag J and others. A preliminary trial of lamivudine for chronic hepatitis B infection. New England Journal of Medicine 333(25):1657-1661. December 21, 1995.

Famciclovir Suppresses Recurrent Genital Herpes

Famciclovir (Famvir) was approved for the treatment of herpes zoster (shingles) in 1994. A recent randomized, double-blind study of 48 HIV positive individuals with recurrent genital herpes simplex found that 500 mg of famciclovir twice a day reduced viral shedding significantly more than placebo. When people are shedding virus, they can potentially spread the disease to others. Volunteers received either famciclovir or placebo for 8 weeks, took no drug for a week, then crossed over to the alternate treatment for another 8 weeks. Famciclovir also appears to reduce the frequency and severity of HSV infection recurrences.

Schacker T and others. Efficacy of famciclovir for suppressing HSV-2 infections among HIV+ persons. 3rd Conference on Retroviruses and Opportunistic Infections. Washington DC. January 28-February 1, 1996. Abstract 13.

Foscarnet Cream for Acyclovir-Resistant Herpes Simplex

Foscarnet (Foscavir) cream (1%) was applied 5 times a day to herpes simplex virus lesions that had previous not responded to acyclovir treatment. Twenty HIV positive people were treated for 6-60 days (the mean number of days was 34.5).

Of the 20 lesions treated, 9 healed completely, 3 showed excellent response (greater than 75% decrease in lesion size), 2 showed good response (greater than 50% decrease), 4 showed partial response (greater than 25% decrease) and 2 had no response. Pain was reduced for 11 of 15 participants who reported pain associated with lesions. Topical 1% foscarnet cream appears to be a safe and effective therapy for acyclovir-resistant herpes simplex lesions in people with HIV.

Hardy D and others. Phase I pilot study of the safety and efficacy of foscarnet (PFA) cream for treatment of acyclovir-unresponsive herpes simplex. 3rd Conference on Retroviruses and Opportunistic Infections. Washington DC. January 28-February 1, 1996. Abstract 167.

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