Published in the Bulletin of Experimental Treatments for AIDS October 1998 issue, by the San Francisco AIDS Foundation.

Part 1:
-- Top 40 Headlines from the World AIDS Conference
-- Trial Analysis
-- Viral Load And DNA Measurement
-- Immune-Based Therapy
-- Protease Inhibitor Side Effects
Part 2:
-- Anti-HIV Drugs and Combinations
Part 3:
-- Salvage Therapies
-- Protease Inhibitor Combinations
-- Opportunistic Infections And HIV-Related Conditions
-- HIV Transmission
-- HIV Prevention

October 1998 Table of Contents

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Selected Highlights from the 12th World AIDS Conference -- Part 3

Harvey S. Bartnof, M.D.

Four-Drug Combination Following Indinavir Failure

• Study included 20 patients in an open-label trial at San Francisco General Hospital
• All had experienced virologic failure (viral load greater than 2,500 copies/mL after more than 24 weeks treatment) with indinavir combination therapy.
• A four-drug combination was used twice daily including nelfinavir at 1,250 mg, soft-gel saquinavir at 1,200 mg, abacavir at 300 mg, and either nevirapine at 200 mg or another nucleoside analog (ten in each arm).
• None had prior therapy with nelfinavir, saquinavir, abacavir, or NNRTIs.
• Median baseline viral load was 4.3 log copies/mL and median CD4 count was 290 cells/mm³.

• After 20 weeks, 66% (6 of 9) in the nevirapine arm had an undetectable viral load (limit 50 copies/mL) compared to only 14% (1 of 7) in the other arm; the median viral load reduction in the abacavir arm was 2.7 log copies/mL compared to 0.6 in the other arm.
• Four patients discontinued due to drug intolerance (one in the abacavir arm, three in the other arm).
• Responses at 20 weeks were significantly correlated with baseline phenotypic drug resistance tests (ViroLogic).
• Those with baseline resistance tests that showed sensitivity to no drugs or one drug had either no or a very minimal viral load reduction (median 0.1 log increase); those with tests that showed sensitivity to 2-3 drugs had a significant viral load reduction (median 2.5 log decrease).
• Four of 20 had baseline tests indicating phenotypic sensitivity to indinavir despite a history of virological failure when taking the drug (possibly minor HIV populations showing resistance were not measured by the test).

• Baseline genotypic testing revealed sensitivity to indinavir in only two of 19.
• These preliminary results indicate initial success with a twice-daily regimen of four drugs from three classes in those whose prior indinavir combination therapy has failed.

Synergism with Ritonavir

• Synergism (enhanced anti-HIV activity) occurs when ritonavir is combined with any of four other protease inhibitor drugs.

Researchers from Harvard Medical School have determined that specific 2-drug and 3-drug combinations of protease inhibitors can lead to synergistic, additive, and even antagonistic (drug effects cancel each other out) results when tested in the laboratory.

Synergistic combinations include saquinavir/amprenavir, saquinavir/ritonavir, ritonavir/amprenavir, and ritonavir/indinavir.

Reports were presented in Geneva on the following new anti-HIV drugs:

• Protease inhibitors: KNI-764 (a.k.a. JE-2147); KNI-241 and KNI-272; Tipranavir (PNU-14060, a non-peptide protease inhibitor)
• Nucleoside analogs: dOTC (BCH-10652); FTC; FddA (see Drug Watch)
• Non-nucleoside reverse transcriptase inhibitors: S-1153; calanolide A

Annual Rectal Pap Smears for Gay/Bisexual HIV-Positive Men are Cost-Effective

• Rectal Pap smear uses the same technique used to detect cervical cancer cells in women (see Human Papillomavirus Infection and Anal Neoplasia, BETA, September 1997).
• HIV-positive men with anal squamous intraepithelial lesions (pre-cancerous cells) are at high risk for progression to anal cancer.
• Men with abnormal anal Pap smears can be referred for treatment.
• Annual screening had a cost-effectiveness ratio of $12,600 per year of life saved, comparable to other well-accepted medical interventions.
• Anal Pap smears will likely provide significant life expectancy gains.

Bacillary Angiomatosis Despite HAART

• Bacillary angiomatosis (cat scratch disease) is a bacterial infection that affects the skin and internal organs; it is caused by Bartonella henselae a bacteria transmitted by infected cat fleas.
• Disease occurred in a patients who had been taking six months of HAART including indinavir, as well as clarithromycin.
• Infection cleared after taking 100 mg doxycycline twice daily for seven months.

Protease Inhibitors Effective Against Candidiasis

• Anti-HIV protease inhibitors are effective against Candida due to direct inhibition of the fungus' aspartyl proteinase enzyme.
• Research was based on vaginal candidiasis in rats.

Primary central nervous system (brain and spinal cord) lymphoma is an AIDS-related opportunistic condition which often has a short survival period. Prior to HAART, brain lymphoma was 3,600 times more common in people with HIV/AIDS. A promising case report from New York Hospital-Cornell Medical Center indicates that there are benefits from HAART for brain lymphoma.

An AIDS patient was found to be comatose with weakness on one side of his body. His CD4 count was six cells/mm³. A magnetic resonance imaging (MRI) scan showed a brain mass. Blood tests for toxoplasmosis antibodies were negative, and a presumptive diagnosis of brain lymphoma was madel this was later confirmed by a brain biopsy. The patient was given standard therapy for lymphoma, including brain irradiation and systemic steroids to reduce brain swelling. At the same time he was started on HAART with indinavir/AZT/3TC.

One and a half years later, the patient is not only alive, but has regained almost all of his neurologic function. His brain MRI scans show no recurrent lymphoma. He has had no opportunistic infections during the same time period, and his CD4 count has risen from six to 266 cells/mm³.

Another interesting case report also indicates that HAART may have some beneficial effects for AIDS-related lymphoma. A bisexual man from France developed AIDS-related non-Hodgkin's lymphoma in the rectum without metastases (spreading). He had a viral load of 5 log copies/mL and a CD4 count of 88 cells/mm³. The cancer completely resolved with high dose lymphoma chemotherapy using ACBVP (Adriamycin [doxorubicin], cyclophosphamide, bleomycin, vincristine, and prednisone). Thereafter, 3-drug anti-HIV therapy was started with indinavir/d4T/3TC. At the same time, two new lymphoma tumors were found next to the scrotum and in the testicle. Yet three weeks later, while receiving only HAART, the lymphoma reportedly resolved. Six months later, a recurrence was noted and interleukin-2 injections were added five times weekly for weeks, while HAART continued. Complete remission occurred three weeks later. Four months later the patient was doing well, with a viral load of less than 67 copies/mL and a CD4 count of 290 cells/mm³.

These two case reports are the first to demonstrate some benefits from HAART for AIDS-related lymphoma.

Researchers from the Sylvester Cancer Institute at the University of Miami have reported remission of AIDS-related brain lymphoma in four of five patients combining HAART with ganciclovir (Cytovene) and interleukin 2. None had prior anti-HIV therapy. The experimental treatment included three drugs, all given twice daily intravenously. Drugs used were AZT at 1,600 mg (this is over five times the standard oral dose), ganciclovir at 5 mg per kilogram, interleukin 2 at two million units, and indinavir and 3TC at standard oral doses. The duration of drug therapy was 2-3 weeks. No patients received brain steroids to decrease brain swelling, which would otherwise be the standard therapy for this type of cancer.

Four of the five patients (80%) responded to the drug therapy alone. Four had a normal brain imaging or computerized tomography (CT) scans. One of the four had radiation therapy and was in complete remission eight months later, while another of the four, who did not receive radiation, was alive after 16 months. Another of the four relapsed five months after starting the 5-drug therapy (with no radiation), but experienced complete remission after re-treatment with the same five drugs. The fourth died six months after responding to drug and radiation thearpy. A fifth of the original patients had improved CT scan findings, became alert, and regained arm and leg movement.

AZT induces apoptosis (programmed cell death) of primary AIDS lymphoma cells in the laboratory. It also causes apoptosis of B-lymphocytes infected with Epstein-Barr virus (EBV) in vitro. EBV is associated with primary brain lymphoma. Ganciclovir, which is FDA-approved for treating cytomegalovirus infection, is also believed to have some activity against EBV. Interleukin 2 is an immune-modulating drug.

This interesting report suggests an alternative and perhaps supplemental approach to treating AIDS-related brain lymphoma. A limitation is the need for twice daily intravenous administration of three of the medications. Each ganciclovir infusion alone takes one hour. Another is the toxic side effects of the drugs.

Nerve Growth Factor for Peripheral Neuropathy

• Recombinant human nerve growth factor was shown to relieve peripheral neuropathy in people with AIDS.

• Expanded access program is planned for 1,800 patients in late 1998.

Peripheral neuropathy occurs in 30% of patients with untreated AIDS. In addition, certain nucleoside analog drugs (d4T, ddI, ddC) cause the condition as a side effect in up to 34% of patients who take them. Peripheral neuropathy is characterized by a painful burning or tingling sensation, primarily in the feet. Nerve fibers undergo degeneration and are inflamed by immune cells. Thus far, treating HIV-related peripheral neuropathy has been difficult. Various types of pain medication and other drugs are used to relieve symptoms.

Nerve growth factor is a molecule necessary for normal nerve function. Recombinant (manufactured) human nerve growth factor has been shown to be effective both in treating peripheral neuropathy associated with diabetes and in preventing toxicity due to cancer chemotherapy drugs. Researchers from the Johns Hopkins School of Medicine reported in Geneva that nerve growth factor is effective for the peripheral neuropathy related to AIDS. Nerve growth factor does not completely eradicate symptoms, nor does it cure the condition; however, it does decrease symptoms significantly.

ACTG 291 enrolled 271 patients with HIV-related sensory peripheral neuropathy. Patients were randomized to receive either 0.1 or 0.3 micrograms per kilogram of human nerve growth factor self-injected under the skin twice weekly, or a placebo. Nerve growth factor was supplied by Genentech. The trial lasted for 18 weeks. Mean baseline CD4 count was approximately 180 cells/mm³ and mean baseline viral load was approximately 3.5 log copies/mL.

Outcome measurements included self reported changes in pain perception using the Gracely Pain Scale (13 incremental ratings of pain severity), the quantity of other pain medications used by the patient, measurements of sensation using the CASE IV device, neurologic physical examination, and overall improvement as determined by the patient and a blinded outside investigator.

The results showed that there was a significant decrease in both average and maximum daily pain intensity scores in those taking either dose of nerve growth factor. The higher dose had a greater pain-reducing effect than the lower one, although the difference did not reach statistical significance. Pain assessments by both patients and blinded investigators showed improvements. However, there were no significant changes in sensory testing, patient-reported mood, or amount of prescription pain medication used. The drug was well-tolerated and led to no significant changes in viral load, CD4 count, or other laboratory measurements.

The most common adverse event was hyperalgesia (increased sensation at the injection site), although this rarely a reason for discontinuation. Patient dropout rate was low. Nerve and muscle aches were reported in a small number of cases, usually due to accidental overdosing of the drug.

Researchers from Washington University Medical Center have reported that three AIDS patients have developed progressive multifocal leukoencephalopathy (PML) even though they had a good response to HAART. PML is a brain infection caused by the JC virus. The rate of PML has decreased markedly with the advent of HAART; prior to the HAART era, PML usually caused dementia and death.

One patient had been taking indinavir/AZT/3TC for 14 months; his viral load had decreased to 3,627 copies/mL and his CD4 count was 100 cells/mm³. The second patient was taking ritonavir/saquinavir/d4T/3TC for five months before being diagnosed with PML; his viral load had decreased to 2,593 copies/mL. The third patient was taking saquinavir/d4T/3TC for 12 months before the onset of PML; his viral load four months

before diagnosis was 8,003 copies/mL and his CD4 count was 151 cells/mm³. Two of the patients died, even though one had an intensification of anti-HIV therapy. The remaining patient was still alive at the time of the report and had responded to the addition of interferon-alpha.

Severe Inflammatory Response after HAART is Improved with Oral Steroid Therapy

• Three patients from Switzerland developed fever, enlarged lymph nodes, and weight loss after adding HAART to their anti-tuberculosis therapy
• The severe inflammatory response was improved with the use of oral steroid therapy with prednisone (20-50 mg daily), an anti-inflammatory drug.
• No other causes of fever were found, including infections or cancers.
• All symptoms resolved ten days after starting prednisone.

HAART Shows Benefits for Multidrug-Resistant Tuberculosis in Argentina

• Three months of indinavir/AZT/3TC were added to second-line anti-tuberculosis combination regimen consisting of cycloserine, clofazimine, ofloxacin, and prothionamide.
• Clinical improvement occurred, in addition to significant increases in CD4 counts and decreases in viral loads, in 17 patients.
• Prior to HAART, multidrug-resistant tuberculosis in people with AIDS was often fatal.

In other reports related to tuberculosis, HAART was associated with a 50% decrease in the tuberculosis rate in São Paolo, Brazil, and daily TMP-SMX treatment was shown to reduce mortality by 44% over two years in 760 tuberculosis patients in Côte d’Ivoire.

Sherwood Gorbach, MD, a leading physician-researcher on AIDS-related wasting and nutrition at Tufts University School of Medicine, has proposed a new definition of AIDS wasting syndrome. Gorbach’s new definition incorporates a percentage of weight loss over time. The current definition was adopted by the Centers for Disease Control and Prevention (CDC) over ten years ago. The existing definition is HIV infection plus involuntary weight loss of more than 10% of baseline weight, plus either chronic diarrhea or chronic weakness and fever for more than 30 days, when no other cause (other than HIV) has been found.

The proposed new definition would include any one of the following:

• Involuntary loss of 3% of body weight in one month
• Involuntary loss of 5% of body weight in 6 months
• Involuntary loss of 10% or more of body weight in 12 months
• A body mass index (BMI) less than 80% of predicted value, if a baseline body weight is unavailable or unreliable; BMI is calculated by dividing body weight in kilograms by the square of the body surface area in meters.

Gorbach stated that the current definition has several limitations. First, no time frame is associated with the syndrome. Second, several studies have revealed that weight loss can occur in the absence of chronic diarrhea, chronic weakness, or fever. Lastly, recent studies indicate that even a 5% weight loss is significant in terms of predicting HIV disease progression. The proposed definition is the recommendation of a group of experts in HIV-associated weight loss and wasting who met in November 1997 to develop a new set of criteria for the syndrome.

Previously, HAART has been shown to decrease the rate of AIDS-related wasting. Wasting has been linked with low blood levels of testosterone, the primary male sex hormone, in persons with HIV/AIDS. Daniel Berger, MD, and colleagues, from the Center for Special Immunology in Chicago, have determined that HAART decreases the rate of low testosterone levels (hypogonadism), which may partially explain the lower rates of wasting syndrome.

The data were compiled from a cross-sectional chart review of 127 male patients (98% gay/bisexual) from a private practice in Chicago. The authors reported that prior to the institution of HAART, 81 of 127 (63%) of their patients had low blood testosterone levels. After HAART was instituted, only 22 of the original 81 (27%) still had low levels. The authors also found that hypogonadism did not significantly correlate with wasting, since 75% of patients with wasting did not have a deficiency in either free or total testosterone. Neither did hypogonadism significantly correlate with viral load or CD4 cell count. The study results are limited by the small number of patients and the study type, which may introduce bias into the results.

Transmission of Multidrug-Resistant HIV

• A gay man in San Francisco acquires HIV strain resistant to all four FDA-approved protease inhibitors.
• Two U.S. military personnel and six newly-infected patients from Geneva have similar resistance profile.
• Case implicates HIV transmission by pre-ejaculatory fluid (pre-cum).
• Implications heighten the importance of safer sexual practices.

Researchers from the University of California at San Francisco (UCSF) have documented recent sexual transmission of an HIV strain that was resistant to the four currently approved protease inhibitor drugs (indinavir, nelfinavir, ritonavir, and saquinavir). The strain was also resistant to two nucleoside analogs, AZT and 3TC. The case was published in the July 30 issue of the New England Journal of Medicine. In the same issue, Anthony Fauci, MD, head of the National Institutes of Allergy and Infectious Diseases, wrote a commentary entitled, "Transmission of multi-drug resistant HIV: The wake-up call."

The case involved a middle-aged gay man (patient 1) who had a documented negative HIV antibody test six months before he developed symptoms of acute HIV infection including fever, night sweats, and fatigue. At that time, his physician found the patient to still have a negative ELISA HIV antibody test, but a positive p24 antigen test. The man stated that he had unprotected anal receptive intercourse four days prior to the onset of his symptoms; however, the insertive partner (patient 2) withdrew prior to ejaculation. Patient 1’s only other risk behavior was protected anal receptive intercourse three months previously with a different partner.

Patient 1 was referred to the UCSF Options Project for people with primary HIV infection. His baseline viral load was greater than 100,000 copies/mL. Despite starting triple combination therapy with nelfinair/AZT/3TC (nelfinavir changed to indinavir after five days), his viral load remained detectable at 3,906 copies/mL after 16 weeks.

Patient 1 contacted the insertive partner, patient 2, who willingly consented to blood testing and medical record review. At various times during 1991-1997, patient 2 had taken eight of the 11 currently available anti-HIV drugs. He admitted poor adherence to his drug therapy regimens. The only three drugs he had not been prescribed were ddI, nevirapine, and nelfinavir. Coincidentally, patient 2 had had a viral load test on the same day he had intercourse with patient 1, and had 28,670 copies/mL.

A highly conserved portion of the envelope of each man's HIV strain was genetically sequenced. The difference between the two patients’ strains was only 1.3% (the mean difference between patient 1’s HIV strain and that of six other randomly selected patients was greater than 7%). The authors concluded that this was partial evidence for recent transmission between the two men. Phenotypic resistance testing indicated that patient 1’s strain was resistant to 4 protease inhibitors plus AZT and 3TC. Both resistant and non-resistant HIV clones were detected in patient 2.

The UCSF researchers also reported that 16% of the other 36 newly-infected patients in the Options Project had one or more resistance mutations to AZT and 8% had resistance to 3TC. A total of 34% had minor, naturally-occurring resistance mutations to protease inhibitors.

Other cases of multidrug-resistant HIV have also been seen. Researchers identified two newly-infected U.S. military personnel with similar protease inhibitor resistance patterns. In addition, researchers from Geneva reported recent transmission of HIV strains resistant to multiple protease inhibitors in six patients. Collectively, these cases are the first to document transmission of protease inhibitor-resistant HIV.

Among the six patients from Geneva, all retained sensitivity to amprenavir, an experimental protease inhibitor likely to be approved by mid-1999.

Patients with multidrug-resistant HIV have much more limited options for anti-HIV therapy. There will undoubtedly be similar reports of sexual transmission of multidrug-resistant HIV in the future. These reports underscore the importance of maintaining safer sexual practices in the era of effective anti-HIV therapy, adherence to regimens in order to minimize the likelihood of developing drug resistance, and the importance of seeking medical care for any flu-like illness that could indicate primary HIV infection. The San Francisco case also indicates that pre-ejaculatory fluid (pre-cum) can transmit HIV and that the withdrawal method is not 100% safe.

Resistance to HIV in Female Sex Workers

• Vaginal secretory immunoglobulin type A (a type of antibody) against HIV was detected in 76% of HIV negative and very few HIV positive female sex workers.
• Vaginal immunoglobulin type G (IgG) against HIV is very low in HIV-resistant female sex workers, yet high in HIV-positive ones.
• Cytotoxic T-cell (CTL) responses to HIV was detected in 53%.
• Blood relatives of HIV-resistant prostitutes are also more likely to be HIV-resistant, suggesting a genetic factor.
• The CCR5 gene mutation is not involved.
• 21 female sex workers from Nairobi, Kenya and five from northern Thailand were studied; all were negative for HIV antibodies and genetic material in their blood.
• This research provides new insights for vaccine design and new treatments.

FDA Approves Glyde Latex Dental Dams for Cunnilingus

• FDA approved the Sheer Glyde Dam, a 10x6 inch thin sheet of scented natural latex, for oral/vaginal sex (cunnilingus); in Australia, the dams are called LOLLYES.
• This is the first product of its kind specifically approved by the FDA for protection against sexually transmitted diseases including HIV.
• U.S. package information states that the dams "are not intended for use during oral/anal sex." However, the Australian package instructions state that, "In oral-anal contact, cover the anus with the dam--always use a new dam if you switch between oral-vaginal and oral-anal sex."
• In North and South America, the exclusive agent for the product is Glyde USA, Inc. Phone 206-283-7664; e-mail glyde@aol.com.

In a written survey of 2,272 HIV negative gay/bisexual men in six U.S. cities:

• 7% of surveyed HIV-negative gay/bisexual men have used the Reality internal female condom for anal intercourse over a 6-month period (16% in San Francisco).
• Problems or concerns reported by receptive partners included pain or discomfort, difficulty inserting the device, difficulty keeping the device in place, and bleeding. Problems or concerns reported by insertive partners included lack of pleasure, difficulty inserting the penis, and difficulty keeping the device in place.
• 72% of receptive users and 85% of insertive users said they were either very or somewhat likely to use the device in the future.

In a separate survey of 100 men who have sex with men in San Francisco sponsored by the Stop AIDS Project and the San Francisco Department of Public Health:

• 86% said they would use the product again.
• Acceptability was higher among men who were HIV-positive, not in monogamous relationships, or had partners of the opposite HIV serostatus.
• Reported negative experiences included difficulty inserting the device (33%), irritation (17%), "bunching up" (12%), unpleasant texture (10%), and noise (9%).
• Reported breakage rate was 0.3% (3 times in 334 episodes of use).

-- Official conference website: www.aids98.ch

-- Audiovisual broadcasts of selected sessions: webcast.aids98.org

-- World Health Communications summaries and reports: www.healthcg.com/hiv

-- Medscape summaries and reports: www.medscape.com/Medscape/
CNO/1998/AIDS/public/index-AIDS.html

-- Conference coverage from The Body HIV/AIDS site:

www.thebody.com/confs/ worldaids698/worldaids698.html

-- Summary from Johns Hopkins University: hopkins-aids/edu/geneva/info.html

Page last updated 6 October 1998

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