Selected Highlights from the
4th Conference on Retroviruses and Opportunistic Infections
(Part III)
by Harvey S. Bartnof, MD
Treatments for Opportunistic Infections, Cancers and Other Conditions
General
HIV Viral Load May Help Predict Opportunistic Infection Risk
Judith Currier, MD, from the University of Nebraska Medical Center, indicated
that HIV viral load measurements, in addition to CD4 cell counts, may
provide information about impending risk for an opportunistic infection
(OI). Data from the DACS 071 study were used. Currently, CD4 threshold
levels are used to determine when antibiotic prophylaxis should be taken
to decrease the risk of a major OI. A CD4 cell count of fewer than 200
cells/mm3 is used as a criterion for instituting prophylaxis
against Pneumocystis carinii pneumonia (PCP). Occasionally, PCP
occurs at a CD4 count greater than 200 cells/mm3. Such patients
would be more likely to have a high HIV viral load.
Currier found that baseline HIV viral load measurements were predictors
of specific opportunistic infections, independent of the CD4 count used
as a predictor for a specific OI. Those OI include PCP, cytomegalovirus
(CMV) and Mycobacterium avium complex (MAC). Further analyses of
major cohort groups will need to be completed; however, future guidelines
for OI prophylaxis will probably include not only CD4 cell threshold levels,
but also HIV viral load thresholds.
Currier JS and others. DACS 071: Correlation of viral
load and risk for opportunistic infections. Abstract and oral presentation
359.
Candidiasis
Oral Intraconazole Solution Beneficial for Fluconazole-Resistant Candidiasis
- Study in San Francisco and Birmingham, AL of 78 HIV positive patients
with oral candidiasis resistant to fluconazole (Diflucan)
- Oral itraconazole (Sporanox) solution 100 mg (10 mL) used twice daily
for 14 days, extended for additional 14 days (for a total of 28 days)
- 55% showed clinical response and 70% showed clinical improvement (less
soreness, less burning, less redness, decreased lesions)
- 23% were cured
- Twice daily dose 3 times weekly is well tolerated and effective in
preventing recurrence
Fessel WJ and others. Itraconazole oral solution for the
treatment of fluconazole-refractory oropharyngeal candidiasis in HIV-positive
patients. Abstract and poster presentation 327.
Moskovitz BL and others. Long-term safety and efficacy
of itraconazole oral solution for treatment of fluconazole-refractory
oropharyngeal candidiasis in HIV-positive patients. Abstract and poster
presentation 325.
Cytomegalovirus
Oral Hydration Equivalent to IV Route for Foscarnet Therapy
Foscarnet (Foscavir) therapy for CMV disease is administered by the intravenous
(IV) route. In order to help prevent kidney toxicity from the drug, adequate
hydration is necessary. Hydration solution has been given intravenously
in the past. Researchers from the Astra Study Group have shown that oral
hydration can be safely used during foscarnet induction therapy, with
a low risk of kidney toxicity in cooperative patients. There were no statistically
significant differences in the number of patients experiencing either
serious adverse events or abnormal increases in kidney function (as inidcated
by creatinine levels) when comparing the 45 patients who received oral
hydration with the 37 patients who received IV hydration. Using the oral
route is expected to save IV infusion time.
Deresinski S and others. Safety of oral versus intravenous
hydration during induction therapy with intravenous Foscavir in AIDS patients
with CMV infections. Abstract and poster presentation 299.
Second Ganciclovir Eye Implant Effective for CMV Retinitis
CMV infection of the eye often leads to blindness if left untreated.
Previous studies have shown that after IV induction therapy with ganciclovir
for CMV retinitis, disease progression occurs after approximately 55 days.
After surgical placement of a ganciclovir eye implant, CMV progression
occurs after approximately 181 days. Researchers from the University of
California at Irvine have reported on a subset of 72 patients who have
received a second ganciclovir eye implant after disease progression occurred
following the first implant. The estimated time to progression after the
second implant was 259 days. Retinal detachment, a treatable condition,
occurred in 15%, while endophthalmitis (severe eyeball infection) occured
in 2%. Retinal detachment also occurs in untreated CMV retinitis. The
authors conclude that a second ganciclovir implant is as effective as
the first one.
Kupperman BD and others. Efficacy of the ganciclovir implant
for the treatment of relapsing cytomegalovirus retinitis. Abstract and
poster presentation 303.
Lobucavir Safety and Efficacy Demonstrated
- Dose-escalating pilot study of 23 patients over 28 days
- Lobucavir was active against most herpes group viruses including CMV,
herpes simplex 1 (cold sores) and 2 (genital ulcers), varicella zoster
virus (shingles), and also against hepatitis B virus
- Dose of 200-400 mg 4 times daily for 1 month was safe and well-tolerated
- 50% decrease in CMV positive urine cultures
- 0.5-1.0 log reduction of CMV in semen
Lalezari J and others. In vitro anti-CMV activity and
safety of oral lobucavir in HIV-infected patients. Abstract and poster
presentation 301.
1263W94 in Phase I Study
- New oral anti-CMV drug
- Drug well tolerated without serious adverse effects
- Side effects include mild to moderate bitter or metallic taste in
mouth, occasional headache and drowsiness
Wang LH and others. A Phase I tolerability and pharmacokinetic
trial of 1263W94, a novel anti-HCMV agent, in HIV-infected volunteers.
Abstract and poster presentation 674.
RS-79070 Dosing Study
- RS-7907 is an oral ganciclovir prodrug
- Once daily dosing (given after a meal) is effective
Brown F and others. Ganciclovir prodrug-multiple dose,
dose-ranging study with effect of food. Abstract and late breaker presentation
LB19.
Cyclic HPMPC in Animal Testing
- Oral cidofovir (Vistide) prodrug, also known as GS 3857
- Drug shows 46% oral bioavailability
- Less kidney toxicity than with cidofovir
Lee WA and others. Safety and pharmacokinetics of an orally
bioavailable prodrug of cyclic HPMPC, a potent nucleotide analog. Abstract
and poster presentation 311.
Dementia
Thioctic Acid (Deprenyl) has Beneficial Effects in HIV-Associated Dementia
Macarthur J. NeuroAIDS. Abstract and state-of-the-art
lecture L5.
Kaposi's Sarcoma
Protease Inhibitors Prevent Untreated Kaposi's Sarcoma Lesions from
Increasing
- Study of topical retinoic acid
Researchers from the University of California at San Diego have determined
that in a study using topical cis-retinoic acid for 22 patients with Kaposi's
sarcoma (KS) skin lesions, patients who were also treated with protease
inhibitor therapy had minimal increases (6-23%) in the size of their untreated
(control) KS lesions. Those who did not take protease inhibitor therapy
had significant increases (79-137%) in the size of their untreated lesions.
A statistically greater proportion (66%) of those taking a protease inhibitors
had no change in the size of their untreated KS lesions compared to those
who were not taking a protease inhibitor (8%). This report, along with
the report in the first section regarding marked improvement in KS following
triple combination therapy including a protease inhibitor drug, underscore
the protease inhibitor-induced beneficial changes in immune function that,
in turn, decreases the growth of KS.
Little S and others. Protease inhibitors are associated
with favorable response to topical treatment of Kaposi's sarcoma. Abstract
and poster presentation 702.
Liposomal Doxorubicin is First-Line Chemotherapy for KS
- Superior to older combination chemotherapy regimens
- Superior tumor response rate
- Superior or equivalent safety profile
Medve M and others. Long term experience with liposomal
doxorubicin as treatment for AIDS-related Kaposi's sarcoma. Abstract and
poster presentation 704.
Northfelt, D and Stewart, S. Doxil (pegylated liposomal
doxorubicin) as first-line therapy of AIDS-related Kaposi's sarcoma (KS):
integrated efficacy and safety results from 2 comparative trials. Abstract
and oral presentation 736.
KSHV is Sensitive to Cidofovir, Foscarnet and Ganciclovir
- Kaposi's sarcoma-associated herpes virus (KSHV) is sensitive to cidofovir
(Vistide), foscarnet (Foscavir) and ganciclovir (Cytovene) in vitro
- KSHV is not susceptible to acyclovir (Zovirax)
Kedes DH and other. Susceptibility of KSHV (HHV8) to antiviral
drugs in culture. Abstract and late breaker presentation LB20.
Non-Hodgkin's Lymphoma
Chronic, High-Dose Acyclovir May Prevent AIDS-Related Lymphoma
A retrospective case-control study has suggested that long-term, high-dose
acyclovir (Zovirax) may help prevent non-Hodgkin's lymphoma (NHL), a common
cancer in people with AIDS. Acyclovir is commonly used to treat herpes
simplex 1 and 2 and herpes zoster (shingles). Acyclovir has antiviral
activity against the Epstein-Barr virus, which is detected in 100% of
primary AIDS-related brain lymphomas and 40-66% of other AIDS-related
lymphomas.
Researchers from the University of Toronto examined the charts of 29
AIDS patients with lymphoma and compared them to 58 control AIDS patients
matched for age, gender, HIV risk factor, duration of AIDS and antiretroviral
drug usage. Chronic, high-dose acyclovir was defined as a dose greater
than or equal to 800 mg daily for more than 1 year.
The results showed that only 2 of 29 (7%) patients with NHL had taken
chronic, high-dose acyclovir, compared with 27 of 58 (46%) of the control
patients. This result was statistically significant. Five of 29 (17%)
of the NHL patients took lower dose or intermittent acyclovir, compared
with 12 of 58 (21%) of controls, a difference that was not statistically
significant. Moreover, 22 of 29 (72%) of the NHL patients did not take
any acyclovir, compared with only 19 of 58 (33%) of the controls, although
this was also not statistically significant.
The authors conclude that high-dose acyclovir may afford some protection
against non-Hodgkin's lymphoma. They are continuing other studies to further
clarify the relationship. Other analyses from large HIV/AIDS cohort studies
would likely help determine whether there is a true decrease in the rate
of lymphoma due to acyclovir usage.
Fong MW and others. Chronic high-dose acyclovir may prevent
AIDS-related lymphoma (NHL): a case control study. Abstract and poster
presentation 709.
Pneumocystis carinii Pneumonia
Fewer Patients Discontinue TMP-SMX when Prophylaxis is Started in Gradual
Doses
Investigators from AIDS Clinical Trials Group (ACTG) 268 reported on
the benefits of using a modified initial dosing of trimethoprim-sulfamethoxazole
(TMP-SMX; brand names Bactrim, Septa and Cotrim) for primary PCP prophylaxis.
The researchers started using very low doses with gradually increasing
increments over a 2-week period, similar to regimens used to desensitize
patients who have demonstrated an "allergy" to the antibiotic
combination. TMP-SMX is recognized as the best regimen to prevent PCP;
unfortunately, the rate of adverse reactions is high among those with
HIV/AIDS, up to 60%.
A total of 377 patients were enrolled, including 14% women, 29% African-Americans
and 8% Hispanics. The graduated dose arm regimen consisted of TMP-SMX
suspension (8 mg TMP plus 40 mg SMX per mL) 1 mL daily for days 1-3, then
2 mL daily for days 4-6, then 5 mL daily for days 7-9, then 10 mL daily
for days 10-12, then 12 mL daily for days 13-14, and then 1 double-strength
(DS) tablet daily for 10 weeks. The standard dose arm took 1 DS tablet
of TMP-SMX daily for 12 weeks. Each arm also took a placebo of the opposite
formulation for the first 2 weeks as a mechanism for placebo-controlling
the study.
Significantly fewer subjects discontinued TMP-SMX over the 12-week observation
period in the graduated dosage arm when compared with the standard DS
tablet arm. However, the time to grade 2 (moderate) or greater toxicities
were similar in both arms. Larger trials are indicated before a specific
recommendation could be made. In the interim, for those patients who can
adhere to the dosing regimen, a graduating dosing with TMP-SMX suspension
for primary PCP prophylaxis may lead to fewer discontinuations of the
drug.
Dohn M and others. ACTG 268 trial -- gradual initiation
of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis
carinii Pneumonia (PCP). Abstract and slide presentation 2.
Trimethoprim Portion of TMP-SMX May Not be Needed for PCP Prophylaxis
Walter Hughes, MD, and colleagues, from St. Jude Children's Research
Hospital in Memphis, TN, have stated that the trimethoprim component of
the combination drug TMP-SMX may not be necessary for PCP prophylaxis.
They continue that TMP may even add to the adverse effects profile of
TMP-SMX in AIDS patients.
Using a steroid-immune suppressed rat model, Hughes found that animals
treated with TMP-SMX developed PCP at the same rate as those treated with
SMX alone. Moreover, PCP developed in 100% of those given TMP (Proloprim)
alone, the same rate as those given a placebo. He said that since the
adverse effects of TMP alone are similar to those of SMX alone, deleting
the TMP component may lead to a lower rate of adverse effects than occur
with the combination. In addition, there would likely be a cost savings.
The authors conclude that clinical trials using SMX alone as PCP prophylaxis
in people with HIV are indicated.
Hughes WT and others. Is trimethoprim of trimethoprim-sulfamethoxazole
(TMP-SMX) necessary for Pneumocystis carinii pneumonia (PCP) prophylaxis?
Abstract and poster presentation 289.
Dapsone Confirmed as Acceptable Substitute if Adverse Reaction to TMP-SMX
Occurs During Prophylaxis
- Retrospective chart review of 60 patients at University of California
at San Francisco
- All patients were HIV positive and had adverse reactions to TMP-SMX
requiring a drug change, and were switched to dapsone. Reactions were
characterized by drug fever, hives, anaphylaxis (shock with life-threatening
low blood pressure), rash or itching
- 13 of 60 (22%) persons had a cross-reaction, i.e., a similar reaction
within 60 days of starting dapsone; 12 of 13 reactions were mild to
moderate, and none required hospitalization
- 4 of those 13 (31%) persons were able to continue taking dapsone despite
the reaction, and the adverse reaction symptoms resolved
- 51 of 60 (85%) were able to maintain PCP prophylaxis with either TMP-SMX
or dapsone
- No demographic or HIV risk factors predicted cross-reactivity
- All patients need screening for glucose 6-phosphate dehydrogenase
(G6PD) deficiency before starting dapsone to avoid the risk of severe
anemia (common in people of Mediterranean ethnicity)
Holtzer C and others. Cross-reactivity and patient outcomes
in HIV-infected patients switched from TMP-SMX to dapsone due to hypersensitivity
reactions. Abstract and poster presentation 292.
Acute PCP Patients May Need to be Isolated from Immunosuppressed Patients
- Documented cases of PCP transmission between AIDS patients
- Documented cases of PCP transmission from AIDS patients to other hospitalized
immunosuppressed patients.
- Second episode of PCP in an AIDS patient due to newly acquired infection,
not reactivation of a previous infection
Wakefield AE. Molecular biological insights into the epidemiology
of Pneumocystis carinii pneumonia. Do patients with P. carinii need to
be isolated? Abstract and oral symposium presentation S3.
Progressive Multifocal Leukoencephalopathy
Interferon-alpha Useful for PML in Retrospective Study
- May delay progression, improve survival and lead to remission
A retrospective observational analysis by Susan Huang, MD, and colleagues,
from Johns Hopkins University in Baltimore, has determined that interferon-alpha
(IFN-alpha) may have striking beneficial effects for progressive multifocal
leukoencephalopathy (PML), a life-threatening brain disease in people
with AIDS due to the JC virus. To date, there have been no effective treatments
for PML, except for occasional reports associated with potent anti-HIV
therapy (see first section).
A total of 104 HIV positive patients with PML diagnosed at their institution
underwent a chart review. IFN-alpha had been taken by 21 patients for
at least 3 weeks. They were compared with 32 PML historical controls with
comparable CD4 counts and "systemic disease."
The median survival of untreated PML patients was 121 days, compared
with 325 days for those who had taken IFN-alpha, a statistically significant
difference. Also, use of IFN-alpha was associated with a significant delay
in developing problems with walking, speech and memory. "Prolonged
remissions" occurred in 33% (7 of 21) of IFN-alpha treated patients,
compared with only short and transient remissions among 12% (4 of 32)
of untreated patients. Marked improvements in magnetic resonance imaging
(MRI) scans occurred among 4 of the IFN-alpha treated patients and none
of the untreated patients.
Other potential confounding factors were not described in the abstract,
including HIV viral loads (in plasma and cerebrospinal fluid) and concomitant
use of antiretroviral drugs. A prospective pilot study using IFN-alpha
for PML would seem warranted. IFN-alpha is used in AIDS care as an adjunct
treatment for Kaposi's sarcoma. It is also used to treat hepatitis C.
Huang S and others. Survival prolongation and symptom
palliation in HIV-seropositive patients with PML treated with alpha-interferon.
Abstract and poster presentation 341.
Wasting Syndrome
Oral Oxandrolone with or without L-Glutamine Improves Wasting
Study 1
- Study done at Brown University in Providence, RI
- Open-label, prospective Phase IV study of 16 patients with wasting
on stable anti-HIV therapy, followed for a mean of 33 days
- Oxandrolone (Oxandrin) 20 mg daily plus L-glutamine 20 gm daily
- L-glutamine is the most common amino acid, and is found in muscle.
Depletion is associated with HIV-wasting; normal glutamine levels are
necessary for muscle synthesis
- All patients had a significant gain in body weight (mean 2.9 kg) and
body cell mass (mean 1.2 kg), as well as an insignificant gain in fat
(mean 0.7 kg)
- Oxandrolone was well-tolerated, with no reported side effects
- Patients will be followed for up to 1 year
Study 2
- Study done at New York City Medical Center
- Open-label study of 21 patients with wasting (20 men, 1 woman) followed
for 120 days. Patients had a baseline CD4 count of 55 cells/mm3
- Oxandrolone was taken 10 mg twice daily
- Mean increases in body weight, body cell mass, fat and intracellular
water, respectively, were:
- 30 days: 6.5 lbs, 3.4 lbs, 1.6 lbs, 1.4 liters
- 60 days: 12.9 lbs, 6.9 lbs, 3.0 lbs, 2.9 liters
- 90 days: 11.3 lbs, 4.2 lbs, 5.2 lbs, 1.8 liters
- 120 days: 16.0 lbs, 6.6 lbs, 6.8 lbs, 2.7 liters
- 30-90 day changes were significant; numbers were too small at 120
days
- Ideal body weight increased from 92% at baseline to 101% at 90 days
- Adverse effects and withdrawal from study not mentioned in abstract
Fisher A and others. Effects of oxandrolone and L-glutamine
on body weight, body cell mass, and body fat in patients with HIV infection-preliminary
analysis. Abstract and poster presentation 692.
Poles MA and others. Oxandrolone as a treatment for AIDS-related
weight loss and wasting. Abstract and poster presentation 695.
HIV Transmission
Orthopedic Surgeon in France Transmits HIV to Patient During Surgery
The French Minister of Health stated last month that an orthopedic surgeon
has very likely transmitted HIV to one of his patients during surgery.
The case was discovered during a "look back" program after the
orthopedist was found to have AIDS. Only 1 of 968 patients who were evaluated
was HIV positive. Genetic sequencing of the HIV strains from the physician
and the patient, performed by the Pasteur Institute, revealed a nearly
identical match, when compared with control strains in the community.
The case report was presented by David Bell, MD, from the Centers for
Disease Control and Prevention (CDC) during a session entitled "Advances
in HIV Prevention."
This case represents the second known health care provider to have transmitted
HIV in an occupational setting. In the past, the CDC has reported that
a Florida dentist with AIDS more than likely transmitted HIV to his patient,
Kimberly Bergalis, and to several other patients during dental surgery.
There have been several other investigations of potential HIV transmission
from infected surgeons to their patients, all of which revealed no transmission.
Bell DM. Prevention of occupational transmission. Abstract
and oral presentation S17.
New Study Indicates 10-100-fold Higher Levels of HIV in Semen Compared
to Prior Reports
- Semen studies of gay men retested with NASBA viral load test finds
1-2 logs higher levels of HIV than previously reported
- Anti-HIV treatment decreases viral load in semen
- Study has implications for sexual transmission
Gupta P and others. High viral load in semen of HIV-1
infected men at all stages of disease and its reduction by antiretroviral
therapy. Abstract and oral presentation 726.
Higher Rates of Heterosexual HIV Transmission in Central Africa Possibly
Explained by Higher HIV Viral Loads in Semen
- Higher semen viral load levels in Malawian HIV positive men than in
U.S. or Swiss Caucasian HIV positive men, even with equivalent CD4 cell
counts
A report by Joseph Eron, MD, and colleagues, from the University of North
Carolina, attempted to explain in part why heterosexual transmission of
HIV in sub-Saharan Africa is believed to occur more frequently than in
developed countries. Several studies indicate that a higher HIV viral
load in semen correlates with an increased risk of heterosexual transmission
to women. The authors measured the HIV viral load in semen from 49 HIV
positive men from Malawi, and 53 similar HIV positive men from Switzerland
or the United States. None had active urethral infection (e.g., gonorrhea
or chlamydia). All the Malawian men acquired HIV by heterosexual contact,
while the U.S. or Swiss men acquired infection either by male-male sex
(30), heterosexual contact (13) or injection drug use (10). No participants
had ever taken antiretroviral therapy. CD4 cell counts were equivalent
in the 2 groups, with a median of 302 (range 67-863) cells/mm3
for the Malawians and a median 320 (range 10-1,220) cells/mm3
in the U.S. and Swiss men.
HIV viral loads were significantly higher in the Malawian group in both
blood plasma and semen plasma (liquid portion without cells). Blood plasma
viral loads were 5.23 log copies/mL for the Malawians and 4.45 log copies/mL
for the U.S. and Swiss men. Semen plasma viral loads were 4.18 log copies/mL
for the Malawians and 3.68 log copies/mL for the U.S. and Swiss men. This
represents a 6-fold higher viral load in blood plasma and a 3-fold higher
median HIV viral load in semen in the Malawian men. Within each group,
the ratio of blood to semen plasma viral load was equivalent. The abstract
did not mention the subtypes of HIV, which was probably different between
the 2 groups. HIV subtype differences have been linked with different
abilities to infect Langerhan's immune cells in the female reproductive
tract. This may represent another co-factor partially explaining the differences
in heterosexual transmission rates for HIV when comparing the developing
to the devloped world.
The Eron study likely underestimates the semen viral load measurements,
according to information presented by C. Rouzioux and colleagues, from
Paris, France. The currently available viral load tests were created to
measure HIV RNA of the B subtype of HIV, which is prevalent in the U.S.,
Europe and Australia. The researchers measured the ability of the 3 commercially
available tests to accurately measure viral load of non-B subtypes of
HIV found elsewhere in the world. They found that the Quantiplex test
(manufactured by Chiron) was accurate, whereas both the Amplicor HIV Monitor
test (manufactured by Roche) and the NASBA test (manufactured by Organon-Teknika)
underestimated viral loads. The Eron study above used the NASBA test.
Eron JJ and others. High levels of HIV-1 in semen and
blood of men in Malawi. Abstract and oral presentation 26.
Rouzioux C and others. Quantification of Ònon-BÓ subtype
HIV-1 RNA: underestimation is frequent for all Ònon-BÓ subtypes with Monitor
and NASBA-QT tests. Abstract and poster presentation 285.
Nevirapine Blocks HIV Transmission to Chimpanzees
- Study has implications for preventing perinatal transmission and for
post-exposure prophylaxis
Grob PM and others. Prophylaxis against HIV-1 infection
in chimpanzees by nevirapine. Abstract and oral presentation 728.
Anti-HIV Activity of Saliva Works by Removing gp120 from HIV Virions
- May explain almost zero risk of HIV transmission by oral-oral contact
("French kissing")
Nagashunmugam T and others. Mechanisms of anti-HIV-1 activity
of human submandibular saliva. Abstract and poster presentation 412.
Women and HIV
Cidofovir Gel Effective for Refractory Anogenital Warts
- Warts due to human papillomavirus
- 18% had a complete response and 48% had a partial response to cidofovir
topical gel after 33 days
- 52% experienced mild-to-moderate side effects of rash, itching, ulceration
and pain
- Responders had 0% recurrence at 3 months and 17% recurrence at 6 months
- Studies are ongoing to determine optimal dosing regimen
- Gel is effective in women and men
Anogenital warts, also called condyloma acuminata, can be extensive,
debilitating and refractory to standard therapies in immunocompromised
people. Anogenital warts are caused by many of the over 100 different
genetic subtypes of human papilloma virus (HPV). Subtypes 16 and 18 are
associated with precancerous changes and occult cancer of the uterine
cervix. HPV infection is also associated with cancer of the anus, the
vulva (external female genitals) and the penis. Cidofovir (Vistide) is
an FDA-approved intravenous drug used to treat of cytomegalovirus (CMV)
disease. It has activity against HPV as well as many herpes group viruses,
including CMV, herpes simplex types 1 and 2, varicella zoster virus (shingles)
and human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus). A new
gel formulation of cidofovir (Forvade) has been developed by Gilead Sciences.
An open-label dose escalation study was undertaken at 9 locations in
the U.S. A total of 67 patients with refractory anogenital warts were
enrolled, including 7 women and 60 men. Past therapies included cryotherapy
(67%), podophyllum (38%), and laser, electrocautery or trichloroacetic
acid (15% each). Perianal warts comprised 76% and labial warts comprised
9% of wart locations. The median number of warts per patient was 8. Three
strengths of cidofovir gel were used: 0.3%, 1% and 3%. Treatment involved
topical application once daily for 5 or 10 days followed by a 2 week observation
period. Two additional treatment cycles were allowed.
Eighteen percent of the patients had a complete response, that is, complete
clearance of the warts (almost all had used the 10 day treatment cycles).
A total of 48% had a partial response, defined as a greater than 50% reduction
in wart surface area. A minor response, defined as a 25-50% decrease in
wart surface area, occurred in 17%. No response, defined as less than
a 25% decrease in wart surface area, occurred in 17%. The median time
to response was 33 days. The recurrence rate in complete responders was
0% at 3 months and 17% at 6 months.
Side effects, including reversible, mild-to-moderate, dose-related application
site reactions, occurred in 52%. Those included swelling, rash, itching,
pain or ulceration. Grade III (severe) application site reactions occurred
in 4%. There were no systemic side effects, and almost no detectable cidofovir
was absorbed into the blood.
The authors concluded that cidofovir topical gel has clinical activity
against anogenital warts, was well tolerated and has no generalized side
effects. Ongoing studies are continuing to determine the best dosage and
length of administration.
Kriesel J and others. A Phase I/II study of cidofovir
gel for refractory condyloma acuminatum in patients with HIV infection.
Abstract and poster presentation 334.
Treatment for Cervical Intraepithelial Neoplasia Increases HIV RNA Viral
Load in Vaginal Secretions
- Likely increases HIV transmission risk to sexual partners
T.C. Wright, MD, and colleagues, from Columbia University in New York
City, have determined that the level of HIV RNA viral load in vaginal
lavage fluids increases as a result of treatment for cervical intraepithelial
neoplasia (CIN) in HIV positive women. CIN is a precancerous lesion of
the uterine cervix that is common among women with HIV.
Six HIV positive women with CIN had vaginal lavage fluids measured for
HIV viral load before, 2 weeks after and 4 weeks after surgery for CIN.
Two women had cryosurgery (freezing), 2 had loop excision and 2 underwent
cone biopsy.
Two weeks after surgery, HIV RNA viral load in vaginal lavage fluids
increased in all 6 patients by a mean 2.4 log copies/mL, while blood plasma
levels increased only slightly, by 0.3 log copies/mL. However, 4 weeks
after surgery, the vaginal viral load levels began to decrease somewhat.
The results suggest that the healing process after surgery involves stimulation
of the immune system, but probably only temporarily, until healing is
complete. The increase in vaginal viral load may represent an increased
risk for transmitting HIV through sexual contact. Safer sexual practices
(i.e., the ue of barrier protection) is recommended.
Wright TC and others. Treatment of CIN increases vaginal
HIV RNA level. Abstract and poster presentation 338.
Antiretroviral Therapy Decreases Vaginal HIV Viral Load
Lennox J and others. Effect of antiretroviral therapy
on vaginal HIV RNA level. Abstract and oral presentation 727.
Perinatal HIV Transmission
Prolonged Rupture of Membranes plus Placental Infection Increases Risk
of Transmission to Newborns
Previous studies have shown that prolonged rupture of membranes ("bag
of waters") during labor for more than 4 hours before birth and infection
of the placenta, or afterbirth (chorioamnionitis), each independently
are associated with an increased risk of transmitting HIV to a newborn.
Researchers at Texas Children's Hospital have determined that when both
conditions are present concurrently, the perinatal transmission risk is
high (38%). When only 1 condition or neither condition was present, the
perinatal transmission risk was much lower (5-6%).
The researchers followed 242 HIV positive pregnant women for 2 years
starting in 1992, before perinatal AZT therapy was in widespread use by
pregnant HIV positive women. The women gave birth to 209 infants. The
overall transmission rate was 9%. The authors did detailed microscopic
examinations of all placentas to determine the presence of placental infection.
They then compared the results with the medical records of events during
labor and the HIV status of the newborns. The results have relevance in
terms of increasing our understanding of perinatal transmission and prevention.
Early detection and treatment of placental infection in HIV positive women
will help decrease HIV transmission to their newborns. Approximately 65%
of perinatal transmission occurs during labor and delivery.
Popek EJ and others. Acute chorioamnionitis and duration
of membrane rupture correlates with vertical transmission of HIV-1. Abstract
and poster presentation 504.
Mathematical Model Identifies Added Risks for Perinatal Transmission
- 4 maternal and delivery risk factors increase transmission rate to
newborns 94-fold
Researchers from the New York City Perinatal HIV Transmission Collaborative
Study Group have used a mathematical model that would explain a 94-fold
increased risk of transmitting HIV from mother to newborn. A total of
775 HIV positive pregnant women and their infants were analyzed between
1985 and 1995. A low CD4 count, no use of AZT during pregnancy, premature
delivery and prolonged rupture of membranes (more than 4 hours) can combine
to increase the risk of perinatal transmission by 94 times.
Matheson PB and others. Recursive partitioning analysis
of maternal and delivery risk factors among 775 HIV-seropositive women
delivering infants in New York City (1985-1995). Abstract and poster presentation
507.
Many Primary Care Physicians Not Following AZT Guidelines for Pregnant
Women
A survey of 678 physicians in California, New York and Florida attempted
to determine the doctors habits of prescribing AZT for their pregnant
HIV positive patients. The survey occurred from January to March of 1995,
and was an attempt to measure the effects of ACTG 076. That study showed
that AZT taken from the fourteenth week of pregnancy and during labor
by the mother, and after birth by the newborn, decreased HIV transmission
by two-thirds. The CDC has since included the regimen as part of their
recommended guidelines for HIV positive pregnant women.
Physicians belonged to the San Francisco Bay Area Community Consortium
and/or the Gay and Lesbian Medical Association, 2 groups that would be
expected to have more knowledge of HIV treatment issues than the average
physician. The response rate was 29%.
Among respondents, 64% in Florida and New York, and 72% in California
were primary care physicians. While 86% indicated that they would recommend
AZT for a pregnant HIV positive woman, only one-half of those would recommend
AZT during the second trimester of pregnancy. Only 64% would recommend
AZT for the infant, as per CDC recommendations. California physicians
and those with more HIV treatment experience were more likely to recommend
AZT for infants. Those physicians who identified as consultants were significantly
more likely to follow the recommended guidelines. The authors concluded
that while many physicians may recommend AZT to their HIV positive pregnant
patients, many were unaware in 1995 of optimal dosing regimens, including
the treatment of newborns.
On a related topic, at the conference in Washington, DC, there were anecdotal
reports that a significant proportion of U.S. obstetrician-gynecologists
still are not encouraging HIV testing of their pregnant patients.
Luber AD and other. Survey of physicians' use of zidovudine
in HIV-infected pregnant females and their newborn infants. Abstract and
poster 513.
Only 2 Doses of Nevirapine May Prevent HIV Transmission to Newborn during
Labor and Delivery
- 1 dose for HIV positive pregnant woman at the onset of labor and 1
dose for the newborn at age 2 days maintains a therapeutic drug level
in the infant for 1 week
- Cost is low enough to be affordable in developing countries
Mark Mirochnik MD, and colleagues, from Boston University School of Medicine,
presented data from the ACTG 250 study, in which 7 HIV positive women
and their 8 infants took nevirapine (Viramune); the aim of the study was
to determine whether perinatal transmission of HIV could be prevented.
Each of the HIV positive pregnant women took 200 mg of nevirapine orally
at the onset of labor, and their 8 newborns took 2 mg/kg orally at a mean
of 56 hours after birth. The newborns were delivered a mean 5.4 hours
after maternal dosing. Drug blood levels in umbilical cords and in infants
were above the therapeutic level throughout the first week of their lives.
There were no observed maternal or infant drug toxicities. The infants
are still too young to determine whether HIV transmission was prevented.
The low cost of such a regimen may be affordable for many developing countries.
Approximately 65% of perinatal HIV transmission occurs during labor and
delivery. ACTG 316 will study the same nevirapine dosing regimen in 800
mother-infant pairs to determine the efficacy of the drug in preventing
HIV perinatal transmission.
Mirochnik M and others. Safety and pharmacokinetics of
nevirapine in neonates born to HIV-infected women. Abstract and oral presentation
723.
Infants and Children
Nelfinavir Phase I study in Infants and Children
- Study participants were 57 HIV positive infants and children
- Sprinkle powder pediatric formula of nevirapine was used
- Adverse effects were similar to those seen in adults, including mild
to moderate diarrhea, with occasional abdominal pain and anemia
- Pediatric patients metabolize the drug faster than adults
- Very limited efficacy data
Krogstad P and others. Phase I study of the HIV protease
inhibitor nelfinavir mesylate in HIV positive children. Abstract and oral
presentation 721.
Ritonavir Phase I/II trial in Infants and Children
- 51 patients for a median of 28 weeks
- Ritonavir liquid formulation taken for 12 weeks (dose escalation during
days 1-5, then in combination with AZT and/or ddI)
- Mean baseline HIV RNA viral load of approximately 5 log copies/mL,
decreased by approximately 3 log after 24 weeks
- Baseline CD4 counts spanned the wide range of 110-404 cells/mm3,
increased by approximately 100 cells/mm3 after 12 weeks,
with further increases after 24 weeks
- 10 of 51 (20%) discontinued the trial because of adverse events (4
had abdominal pain, vomiting and diarrhea; 3 had severe liver enzyme
elevations; 1 refused to continue; 1 had a stroke after a history of
prior strokes)
- Taste was a "minor problem" in the first 2 weeks
- Dose was 250-400 mg/m2 every 12 hours
- Abbott has requested FDA approval for ritonavir in children with HIV/AIDS
Mueller BU and others. Update on the pediatric Phase I/II
study of the protease inhibitor ritonavir (ABT-538). Abstract and oral
presentation 722.
Triple Therapy Update: Nevirapine, AZT plus ddI for 6 Infants after
18 Months
- Female twin remains negative by HIV ELISA antibody test
- Male twin has since seroreverted to HIV antibody positive, with an
increase in his HIV viral load
- Study ACTG 180
An update on triple anti-HIV therapy for infants, first reported at the
XI International Conference on AIDS (see BETA, September 1996, page 12),
was presented at the Washington conference. K. Luzuriaga, MD, and colleagues,
from the University of Massachusetts, presented data on HIV positive infants
treated with nevirapine plus AZT plus ddI from age 2.5 months until age
18 months. For 6 of the 8 infants, HIV RNA viral load decreased from a
range of 41,516-1,546,242 copies/mL to a range of 5,542-180,000 copies/mL.
After 5.5 months, viral load began to rebound in 3 of the 6 infants. Those
3 had developed resistance to nevirapine.
There were 2 fraternal twins (the other 2 of the original 8) whose viral
loads decreased from approximately 300,000 copies/mL to undetectable (limit
of detection 10 copies/mL) after 5.5 months. After 11 months, their ELISA
HIV antibody tests became negative. Their Western Blot antibody bands
had faded significantly and became indeterminate, suggesting an extremely
low level of total body HIV antigen.
After 18 months of follow-up, the female twin has remained HIV negative
by ELISA. However, the male twin has since had an increase in his viral
load, and seroreverted to HIV positive on his antibody tests. His therapy
has been changed to ritonavir. Both twins still have HIV DNA in their
blood mononuclear cells. Researchers will follow all 8 infants.
BETA: 12. September 1996.
Luzuriaga K and others. Triple combination therapy in
early vertical HIV-1 infection: potential for eradication of infection.
Abstract and oral presentation 725.
d4T Monotherapy is Better than AZT Monotherapy for Infants and Children
- Double-blind, randomized study of 216 symptomatic children up to 6
years of age; patients on study for a median of 17 months
- Significantly more gain in weight in d4T than in AZT arm
- Significantly less neutropenia in d4T vs AZT arm
- Significantly greater increases in mean CD4 cell counts in d4T arm
vs AZT arm
- No differences in HIV disease progression
Klein MW and others. A randomized comparative trial of
zidovudine (AZT) versus stavudine (d4T) in children with HIV infection.
Abstract and oral presentation 724.
ddC Monotherapy in Children for 96 Weeks Leads to Resistance in Only
4%
- Study ACTG 138
- 23 children with symptomatic disease who had progression or were intolerant
to AZT were switched to ddC monotherapy for median 96 weeks
- Reversion of syncitium-inducing (SI) to non-SI HIV phenotype in 4
of 19 (21%) of evaluated children.
Viani RM and other. HIV-1 phenotypes in children with
advanced disease treated with long-term zalcitabine. Abstract and poster
presentation 566. .
Vaccines
Canarypox HIV Vector Vaccine Followed by gp120-SF Vaccine Induces Both
Cytotoxic and Neutralizing Antibody Responses to HIV
- Phase I/II randomized study of 76 HIV negative healthy volunteers
for up to 12 months
- Extension of the trial is warranted to groups at higher risk for HIV
Corey L and others. Combination candidate HIV vaccines
using a canarypox vector followed by boosting with gp120SF-2. Abstract
and late breaker presentation LB18.
Epidemiology Update
Worldwide
- In 1997, it is projected that 8,500 new HIV infections will occur
globally each day, including:
- 3,000 women (40% of adults)
- 1,000 newborns
- 90% in developing countries
- 50% of adults between the ages 15-25 years (3,750 persons each day)
- In 1996, there were 3.1 million new HIV infections globally, including
13% in infants
- As of December 1996, there were 22.6 million living persons with HIV
or AIDS
- In 1996, there were greater than 1 million deaths due to AIDS, representing
25% of AIDS-related deaths since the start of the epidemic
United States
- Between 1990 and 1995, the AIDS incidence rate in persons aged 13-25
years increased 20%
- In the same period, the AIDS incidence rate in heterosexuals ages
13-25 years increased 130%
- AIDS incidence remained the same for young gay/bisexual men and injection
drug users
- AIDS incidence rate in young women 13-25 years increased by 70%; the
rate remained the same for young men
- AIDS incident rate in young African Americans increased 50%. The rate
increased 20% in young Hispanics. The rate declined slightly then remained
the same for young white persons
Henning P and others. Estimating recent patterns of HIV
infection among adolescents and young adults. Abstract and oral presentation
375.
Piot P. HIV/AIDS: the global status and response to the
epidemic. Plenary lecture-oral presentation S2.
Harvey S. Bartnof has been a member of the Scientific Advisory Committee
at the San Francisco AIDS Foundation since 1987.
Page last updated 1 April 1997
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