Published in the Bulletin of Experimental Treatments for AIDS Winter 2001 issue, by the San Francisco AIDS Foundation.

Winter 2001 Table of Contents

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Open Clinical Trials for HIV/AIDS Treatments

Christopher Gortner

Antiretroviral Therapy

Abacavir (Ziagen)

This Phase II study will evaluate whether the addition of abacavir to an anti-HIV drug combination that includes at least three approved antiretroviral drugs can lower viral load levels to undetectable (below 50 copies/mL). Investigators will also evaluate side effects in this double-blinded, placebo-controlled study. Participants will be assigned to one of two treatment groups: one group will add abacavir 60 to 90 days after having started an antiretroviral regimen; the second group will add a placebo (sugar pill). Regular clinic visits are required. Participants whose viral loads do not respond to treatment will be discontinued from the blinded part of the study. If treatment failure occurs after week 12 of the study, participants will be offered the opportunity to take abacavir until the study's conclusion (week 36). Eligible participants must have been taking an accepted anti-HIV regimen composed of at least three antiretroviral drugs for at least 28 days before study entry. Participants must also have a viral load greater than 500 copies/mL but less than 10,000 copies/mL. Exclusion criteria include prior use of abacavir, use of any anti-HIV treatment for more than 90 days, and use of St. John's wort. Study locations include Atlanta (404-616-0654), Baltimore (410-955-4370), Chicago (312-572-4545), Cincinnati (513-584-8373), Dallas (214-590-0414), Miami (305-243-3841), New York (212-448-5126), San Juan (787-767-9192), Seattle (206-731-8877), and Stanford (650-723-2804). (ACTG A5064).

DPC 083, NRTIs

This Phase II study will help to determine the safety and tolerability of DPC 083 (an experimental non-nucleoside reverse transcriptase inhibitor, or NNRTI) in combination with two nucleoside analogs (NRTIs) in people who are experiencing treatment failure while taking an anti-HIV regimen that includes an approved NNRTI. In addition to efficacy, this open-label study will evaluate side effects. Participants will take DPC 083 in combination with two NRTIs selected by the researchers; physical examinations and laboratory tests will be administered during weeks 8 and 24 of the study. Follow-up clinic visits will be scheduled one and three months after study conclusion. Eligible participants must weigh at least 50 kg (110 lbs), have a viral load of at least 1,000 copies/mL within 45 days prior to the first day of the study, and have an HIV genotypic screening done while taking their failed NNRTI regimen or within two weeks of stopping treatment. Participants must also agree to practice an effective method of birth control for the duration of the study. Exclusion criteria include virologic failure resulting from use of any protease inhibitor (PI) drug, use of illegal injection drugs within six months of study entry, pregnancy, or breast-feeding. Study locations include Chicago (773-296-2400), Kansas City (816-235-1953), Newport Beach (949-646-1111), and Tampa (813-870-4760). (314A; DPC 083-203)

Interleukin 2 (IL-2)

This Phase III, open-label, and randomized study will help to determine whether the use of IL-2, in combination with an anti-HIV regimen, can reduce the risk of serious AIDS-related infections and/or prolong survival in HIV-infected people. IL-2 is a protein produced by lymphocytes. In various clinical trials, IL-2 has demonstrated a capacity for increasing CD4 cell counts. Study participants will be randomly divided into one of two treatment groups. Group 1 will take a combination antiretroviral regimen without IL-2. Group 2 will take a combination antiretroviral regimen plus IL-2, administered as an injection under the skin twice a day for five days. The five-day cycle will be repeated every eight weeks for three cycles; subsequent cycles will be based on individual response. Regular physical examinations and blood tests are included and participants will be taught how to self-administer IL-2. The study will last for six years, with regular clinic visits required. Eligible participants must have a CD4 cell count of at least 300 cells/mm3 and be taking a stable (unchanged) combination anti-HIV regimen. Exclusion criteria include prior use of IL-2, a history of AIDS-defining illnesses, and pregnancy. The study is being offered at the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda (1-800-411-1222). (00-I-0071)

T-20 (Pentafuside), Abacavir, Ritonavir (Norvir), Amprenavir (Agenerase), and Efavirenz (Sustiva)

This Phase II trial will evaluate three doses of T-20, an experimental anti-HIV fusion inhibitor, in combination with abacavir (an NRTI), ritonavir, and amprenavir (PIs), and efavirenz (an NNRTI). Participants will be assigned to one of four treatment groups. Three of the groups will take abacavir, amprenavir, ritonavir, and efavirenz, plus three different doses of T-20. The fourth group will take the same antiretroviral regimen without T-20. The study will last for one year. Eligible participants must have a viral load between 400 and 100,000 copies/mL and have taken at least one PI drug for at least 16 weeks. Participants must also agree to practice sexual abstinence or use at least two effective methods of birth control for the duration of the study. Exclusion criteria include prior use of any NNRTI, prior use of any of the study medications except ritonavir, pregnancy, and breast-feeding. Study locations include Atlanta (404-876-2317), Austin (512-480-9660), Fort Lauderdale (954-524-2250), Los Angeles (310-825-1301), Pittsburgh (412-647-8125), San Diego (619-543-8080), San Francisco (415-474-4440), and Tulsa (918-743-1006). (295B; T-20-206).

Ritonavir, Amprenavir

This open-label cohort study will determine if salvage treatment with an anti-HIV regimen that includes two PI drugs-ritonavir and amprenavir-is safe and can lower viral load levels in people who no longer experience benefits from a regimen that included nelfinavir. Eligible participants must have a viral load of 1,000 copies/mL or greater and have taken prior anti-HIV treatment for more than 12 weeks. In addition, participants must have experienced viral breakthrough while taking a previous anti-HIV regimen containing nelfinavir as the only PI. Exclusion criteria include intolerance to ritonavir, liver disease or damage, use of any PI drug except nelfinavir, and use of various anti-tuberculosis (anti-TB) medications. The study is being offered in Houston (713-526-9821). (313A; APV-430).

Hydroxyurea (Hydrea), ddI

This Phase II, double-blinded, and placebo-controlled study will evaluate whether the addition of hydroxyurea to an anti-HIV combination regimen that includes ddI can suppress the virus in people with advanced HIV disease who have experienced virological failure while taking a first or second triple combination regimen. Participants will be tested to determine their response to ddI. Anti-HIV drug combinations will be selected based on individual responses to ddI and history of prior antiretroviral use. The study will last for 48 weeks. At week five, all participants willing to start anti-HIV treatment will be assigned at random to one of three treatment groups. The first group will take their selected anti-HIV drugs in combination with a hydroxyurea placebo and ddI. The second group will take their anti-HIV drugs plus ddI, and will start hydroxyurea after a delay of eight weeks; the third group will take their anti-HIV drugs plus ddI and hydroxyurea.

Eligible participants must have been unable to achieve viral suppression while taking one or two anti-HIV regimens that included at least three anti-HIV drugs. They must also have been on a stable triple anti-HIV combination regimen for at least sixteen weeks prior to study entry. In addition, eligible participants must have a CD4 cell count below 300 cells/mm3 within 45 days of study entry and agree to use two methods of effective birth control while on study drugs and for at least 60 days after stopping the drugs. Participants will receive tests to measure viral load response and drug side effects. Exclusion criteria include a serious infection or illness that requires treatment within two weeks prior to study entry, use of hydroxyurea within 24 weeks prior to study entry, pregnancy, and breast-feeding. Study locations include Rockville (301-230-3150) and Stanford (650-732-2804). (ACTG A5609)

Strategic Treatment Interruption (STI)

Intermittent vs Continuous Treatment

This Phase IV study will evaluate the effects of intermittent versus continuous anti-HIV treatment, with the goal of achieving durable viral suppression and improving quality of life while minimizing drug toxicity and side effects. Participants will be assigned to one of two cohorts. Cohort 1 will be comprised of 35 individuals who take continuous HAART, with intervals of one month off treatment followed by two months on treatment. Cohort 2 of 10 individuals will be divided into two sections of five participants each. These sections will take shorter on-off treatment cycles to evaluate the effects on viral suppression and specific anti-HIV immune response. Laboratory tests will include CD4 cell counts, viral load, toxicity and side effects, HIV-specific immune responses, and viral resistance. Eligible participants must have a CD4 cell count of at least 300 cells/mm3 within 30 days of study entry; for participants in cohort 2, the lowest documented CD4 cell count must be no fewer than 200 cells/mm3. In addition, eligible participants must be taking an antiretroviral regimen that includes at least two NRTIs and an NNRTI or a PI, and have at least one viral load test below 500 copies/mL, with a confirmatory viral load of less than 50 copies/mL prior to study enrollment. Exclusion criteria include no history or laboratory evidence of hepatitis B (HBV) infection, no active substance abuse, no evidence of clinical resistance to approved antiretrovirals, and no use of nevirapine for participants interested in cohort 1. The study is being offered at NIAID in Bethesda (800-411-1222). (00-I-0020)

Multidrug Resistance and STI

This randomized study will evaluate the benefits and/or drawbacks of changing to a new antiretroviral regimen immediately or after first taking a four-month treatment "holiday" in people who appear to be resistant to several anti-HIV medications. All interested participants will receive a genotypic screening test; if the test reveals multidrug-resistant virus, they will be considered eligible for the study. Eligible participants will then receive phenotypic testing to determine which drugs they are resistant or sensitive to, and be assigned at random to either start a new antiretroviral regimen or stop taking all anti-HIV medications for a period of no more than four months. After four months, they will start a new antiretroviral regimen. Clinic visits are required during the two-year study period. In addition to the criteria already mentioned, eligible participants must have a viral load greater than 10,000 copies/mL and be taking a stable antiretroviral regimen for at least 14 days prior to genotypic testing. Exclusion criteria include opportunistic infections (OIs), vaccinations administered 14 days prior to genotypic testing, pregnancy, and breast-feeding. Study locations include Atlanta (404-876-2317), Chicago (773-244-5800), Denver (303-436-7195), New Jersey (973-483-3444), New Orleans (504-584-1971), and Portland (503-229-8428). (CPCRA 064)

Other Conditions

Herpes: Valacyclovir (Valtrex)

This Phase III study will evaluate if valacyclovir is a safe and effective treatment for anogenital herpes (herpes simplex virus [HSV] infection of the anus and external genitals) in people with HIV. Participants will be assigned at random to receive either valacyclovir or placebo twice a day for six months, with monthly clinic visits required. Participants who suffer a recurrence of anogenital herpes will be offered valacyclovir twice a day for five days. Eligible participants must have HSV-2 infection, have taken antiretroviral combination treatment for at least two months before entering the study, and have had four or more recurrences of HSV lesions in the last 12 months. Exclusion criteria include sensitivity to acyclovir (Zovirax), unhealed HSV lesions at study entry, and use of other anti-herpes medications. Study locations include Charlotte (704-342-8102), Fort Lauderdale (954-767-2130), Houston (713-793-2939), Los Angeles (323-930-2324), Montreal (514-524-3642), Providence (401-454-6969), and San Francisco (415-474-4440). (104C; HS230018)

Hepatitis C (HCV): Ribavirin, Interferon
Alfa-2a (IFN-alfa), Pegylated Interferon
(PEG-Intron)

This Phase II/III study will compare the effectiveness, safety, and tolerability of two hepatitis C treatments in people coinfected with HCV and HIV to determine if pegylated interferon (PEG Intron) plus ribavirin, an antiretroviral, is more effective than interferon alfa-2a (IFN alfa-2a) plus ribavirin. PEG Intron is a modified formulation of IFN alfa-2a with a longer half-life that reduces frequency of treatment. Participants will be assigned at random to one of two treatment groups for up to 48 weeks of treatment. Group 1 will take IFN alfa-2a plus ribavirin, and group 2 will take PEG Intron plus ribavirin. Laboratory tests will be administered at week 24 to monitor participant response to treatment; if treatment is considered ineffective, it will be discontinued. If treatment is effective, it will be continued for an additional 24 weeks. Eligible participants must have chronic liver disease consistent with HCV infection and meet one of the following sets of guidelines: 1) CD4 cell count greater than 100 cells/mm3, viral load below 10,000 copies/mL within 35 days prior to study entry, stable antiretroviral treatment for 12 weeks prior to study entry, with intent to continue treatment for 24 weeks after study entry; or 2) CD4 cell count greater than 300 cells/mm3 within 35 days prior to study entry, no antiretroviral treatment 12 weeks prior to study entry, and no intention of starting treatment within the first 24 weeks of study entry. Exclusion criteria include a positive test for HBV, severe mental illness, and prior use of interferon or oral ribavirin. Study locations include Boston (617-726-3819), Chicago (312-926-4655), Dallas (214-590-0414), Iowa City (319-353-8441), Miami (305-926-4655), New Orleans (504-584-3566), and San Francisco (415-514-0550). (ACTG A5071)

Body Fat Redistribution: 3TC (Epivir), Abacavir, AZT (Retrovir)/3TC (Combivir)

This Phase IV study will evaluate whether taking abacavir, abacavir plus 3TC, or AZT/3TC (in the Combivir formulation) can improve increased lactic acid levels and abnormal fat redistribution in people who are taking an anti-HIV regimen that includes d4T (stavudine). Participants will be randomly divided into two treatment groups: those who have never taken AZT will substitute Combivir for d4T, and those with prior AZT experience or AZT intolerance will substitute abacavir for d4T. Regular laboratory tests will include biopsies (removal) of tissue samples and blood tests to measure any changes in lactic acid and body fat levels. The study will last 48 weeks. Eligible participants must have had a viral load of fewer than 400 copies/mL on their two most recent tests, and either 1) a decrease in facial fat, decrease of fat in lower limbs, and decrease of fat in buttocks area, or 2) an increase in lactate level greater than 2.2 mmol/L at the screening visit, plus two additional symptoms. Eligible participants must also have taken d4T consistently for six months prior to study entry. Exclusion criteria include use of abacavir plus Combivir or AZT, pregnancy, or breast-feeding. Study locations include Brooklyn (718-237-8865), Cleveland (216-844-8051), Fort Lauderdale (954-467-3006), Houston (713-961-7191), Los Angeles (310-358-2300),New York (212-420-1303), and Seattle (206-386-2820). (238T; ESS40010)

Vaccines

APL 400-003

This Phase I study will determine the safety and immunogenicity of APL 400-003, a DNA vaccine encoding the HIV-1 env and rev genes, in HIV negative participants. The vaccine is designed to prevent HIV infection and will be tested in four different doses: 100, 300, 1,000, and 3,000 µg. The study also includes a control (placebo) arm. Immunizations will be given on day 1 and weeks 4 and 8 of the study, with a booster administered at week 24. Clinical and laboratory parameters will be measured, with a follow-up of one year for participants who complete the study. Eligible participants must be HIV negative and have no known hypersensitivity to local anesthetics, among other extensive criteria. The study is being offered in Bethesda (800-411-1222). (96-I-0050)

ALVAC-HIV, gp160 MN/LAI-2

This Phase I/II, open-label study will evaluate whether two experimental vaccines, ALVAC-HIV and gp160 MN/LAI-2, can safely and effectively boost the body's immune response to HIV in HIV positive people who have been taking antiretroviral therapy for at least two years. Participants will remain on their current anti-HIV regimens for the duration of the study. All participants will receive injections with the vaccines on days 0, 30, 90, and 180 of the study. Regular physical examinations and blood tests will be provided. Eligible participants must have a viral load of below 50 copies/mL and have been taking an anti-HIV regimen for at least two years. The study is being offered in New York (212-448-5020). (AIEDRP AI-04-006)

Women and Gender Studies

Indinavir (Crixivan), Ritonavir, ddI EC, d4T

This open-label, Phase III study will evaluate the safety and efficacy of the multidrug anti-HIV regimen of indinavir, ritonavir, enteric-coated ddI, and d4T in people who have taken prior anti-HIV treatment. The study will also attempt to determine if men and women experience gender-based differences in their responses to the regimen. All participants will receive the combination regimen; some participants may receive additional drug and hormone level tests. Eligible participants must have a viral load greater than 50 copies/mL, have taken prior anti-HIV treatment with an NNRTI/NRTI combination or an NRTI combination for more than eight weeks, or have stopped treatment for a maximum of 12 weeks or less. Exclusion criteria include prior use of a PI drug for more than 14 days and prior use of ddI or d4T for more than 30 days. Study locations include Berkeley (510-204-1291), Boston (617-482-9485), Dallas (214-648-9296), Fort Lauderdale (954-467-3006), Los Angeles (323-343-8280), Machuelo Ponce, PR (787-259-4046), and New York (212-939-2926). (312A; BMS 2000)

AT LAST Study: ddI EC, d4T, Indinavir, Ritonavir

This study will evaluate the combination regimen of the nucleoside analogs ddI EC and d4T plus two PIs, indinavir and ritonavir, in women with prior use of both NRTIs and NNRTIs, but not PIs. The 48-week study will determine if the above drugs cause changes in body fat, as well as glucose, insulin, cholesterol, or triglyceride blood levels, and compare those changes by gender. The study will also attempt to determine if there is a gender difference in safety, tolerability, and efficacy of the regimen. Participants will be assigned to receive indinavir, ritonavir, d4T, and standard (noncoated) ddI. After four weeks of treatment, all participants will switch from standard ddI to ddI EC; there are no placebos in the study. Clinic visits are required every two weeks; one all-day visit may also be required. In addition, hormone levels will be measured in some participants to evaluate the effect that PI therapy may have on women. The organization Women Alive will provide peer support to participants. Although there is no CD4 cell requirement, eligible participants must have a viral load of at least 500 copies/mL and prior NNRTI and NRTI experience, excluding more than 30 days' use of ddI and d4T. Exclusion criteria also include more than 14 days' use of a PI. Study locations include Berkeley (510-204-4109) and Chapel Hill (919-966-7883).

Nelfinavir, AZT, 3TC

This Phase I study will evaluate the safety and tolerability of the anti-HIV combination of nelfinavir, AZT, and 3TC, and its ability to prevent perinatal (mother-to-child) HIV transmission in HIV-infected pregnant women. Pregnant participants will receive nelfinavir, AZT, and 3TC at study entry until 12 weeks after delivery. Their babies will receive the same combination for 16 weeks, starting at approximately 12 hours after birth. Blood tests will be collected regularly from mothers and babies to measure drug levels and HIV levels. Mothers will be observed for three months after giving birth, babies for five to six months. Participants may continue to take nelfinavir for an additional six months. Eligible participants must be at least 13 years of age, be in the second or third trimester (14-34 weeks) of pregnancy, and have a normal ultrasound exam. Exclusion criteria include intolerance to AZT or 3TC, an active OI or bacterial infection, intention to breast-feed, and known risk for premature birth or pregnancy complications. Study locations include Baltimore (410-706-8732), Boston (617-355-8198), Chicago (312-572-4547), Jacksonville (904-244-5331), La Jolla (619-534-7170), Los Angeles (310-206-6369), San Juan (809-764-3083), and Washington, DC (202-865-1248). (ACTG 353)

Children and Adolescents

Hydroxyurea, Efavirenz, ddI, d4T

This pilot study will evaluate the benefits of adding hydroxyurea, an anticancer drug, to two NRTIs (d4T and ddI) plus an NNRTI (efavirenz). The study will attempt to determine the safety, tolerability, and efficacy of the four-drug regimen in children and adolescents (3--21 years of age). Eligible participants must stop all antiretroviral treatments two weeks prior to study entry. All participants will take d4T, ddI, and efavirenz; they will be assigned at random on day 1 or week 6 to receive hydroxyurea. Blood tests will be administered on days 1, 3, 5, and 7 to measure how the medications are affecting the body. This one-year study requires clinic visits every three weeks for the first three months, and once a month thereafter. Eligible participants must have a viral load of at least 10,000 copies/mL; there is no CD4 cell requirement. Exclusion criteria include prior use of hydroxyurea, active or past peripheral neuropathy related to antiretroviral treatment, and current use of G-CSF (filgrastim, Neupogen) or GM-CSF. This study is being offered in Bethesda (301-402-1391). (NCI 99 C-1118)

Ritonavir, Nevirapine, d4T

This Phase II pilot study will evaluate the safety and efficacy of ritonavir, nevirapine, and d4T, and their ability to effect immune reconstitution in HIV positive children. All children will receive the regimen or predefined drug substitutions in the case of intolerance. Laboratory tests will include CD4 cell and naive T-cell levels. Eligible participants must be between 14 and 18 years of age and be considered clinically stable. Exclusion criteria include history of AIDS-defining illnesses and prior use of d4T. Prior use of ritonavir, indinavir, or nelfinavir for less than four weeks is allowed. The study is being offered in Bethesda (1-800-411-1222). (98-C-0041)

Christopher Gortner is the Editor of Spanish BETA.

Page last updated 20 March 2001