BETA September 1997.
by Harvey S. Bartnof, MD
Treatments for HIV Disease
Kidney/Urinary Abnormalities Due to Indinavir
Kopp JB and others. Crystalluria and urinary tract abnormalities associated with indinavir. Annals of Internal Medicine 127(2):119-125. July 15, 1997.
Indinavir Therapy Improves Certain Blood Counts
BETA: 29-31. March 1997.
Tozzi V and others. Effects of indinavir treatment on platelet and neutrophil counts in patients with advanced HIV disease. AIDS 11(8):106 7-1068. 1997.
New Saquinavir Formula More Potent than Original
A new soft-gel capsule formulation of saquinavir (Fortovase) is expected to receive FDA approval by the end of 1997 (see BETA, June 1997, page 8). An interim analysis of the NV 15355 study reveals superior benefits of the new soft-gel capsule when compared with the current hard-gel capsule formulation (Invirase). A total of 171 HIV positive patients were enrolled in the study. None had received prior HIV treatment. Participants had baseline HIV RNA viral load levels greater than or equal to 5,000 copies/mL. Participants were randomized to receive either hard-gel saquinavir at 600 mg every 8 hours or soft-gel saquinavir at 1,200 mg every 8 hours. Both arms were required to combine their saquinavir with 2 nucleoside analog drugs of choice. After 16 weeks, enrollees were allowed to cross over to the opposite formulation or maintain their original formulation. Participants will be followed for at least 48 weeks.
The mean entry HIV RNA viral load was 4.8 log copies/mL, while the mean CD4 count was 401 cells/mm3 for the hard-gel arm and 447 cells/mm3 for the soft-gel arm. Demographics including age, gender and race were similar in both groups.
Using the Roche Amplicor RT-PCR test with a limit of detection of 400 copies/mL, a significant difference was found after 16 weeks of treatment. Eighty percent of participants in the soft-gel arm achieved an undetectable viral load, compared with only 43% in the hard-gel arm. The mean decrease from baseline was 2.0 log copies/mL in the soft-gel arm, compared to 1.6 log copies/mL in the hard-gel arm. CD4 cell count changes were not reported.
No serious adverse events or deaths were reported as a result of saquinavir. Other studies using the new formulation of saquinavir are expected to be released at the upcoming Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in late September.
NV15355-A randomized, parallel arm, comparative, open-label, multicenter study of the activity and safety of two formulations of saquinavir in combination with two nucleoside antiretroviral drugs in treatment naive patients. Executive Summary. July 18, 1997.
Antagonism of Indinavir and Saquinavir Confirmed
Double protease inhibitor combinations have demonstrated efficacy in some HIV positive patients who do not respond to or are intolerant of regimens containing a single protease inhibitor. The most commonly used combination is ritonavir (Norvir) plus saquinavir.
Researchers from Harvard Medical School have documented that combining indinavir with saquinavir in vitro leads to antagonistic drug effects. Specifically, the anti-HIV effects are less potent than what would be expected from adding the anti-HIV effects of each drug alone. Laboratory strains tested included a strain never exposed to antiretroviral drugs, as well as an AZT-resistant strain and a strain resistant to all FDA-approved nucleoside analog drugs. The authors concluded that their findings do not necessarily indicate that the 2 drugs could not be used together in patients. However, additional research in vivo would be necessary before routine usage in patients could be recommended.
These data conflict with a report from the recent St. Petersburg conference on HIV eradication. One patient with multiple resistance to all FDA-approved nucleoside analog drugs did achieve an undetectable viral load after starting double combination therapy with indinavir and saquinavir (doses not stated). Additional research will help to resolve this apparent conflict.
Merrill DP and others. Antagonism between human immunodeficiency virus type 1 protease inhibitors indinavir and saquinavir in vitro. Journal of Infectious Diseases 176:265-268. July 1997.
Schmit JC and others. Multiple dideoxynucleoside analogue-resistant HIV-1 in Europe. In: Program and Abstracts from the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication. St. Petersburg, FL. June 25-28, 1997. Abstract 38.
Indinavir Combination Therapy Decreases AIDS Progression and Death
AIDS Clinical Trials Group (ACTG) Study 320 has been terminated prematurely by an independent data safety and monitoring board because of significant findings in one study arm. The randomized, placebo-controlled trial compared AZT (Retrovir) at 600 mg daily plus 3TC (Epivir) at 300 mg daily to the same 2 drugs plus indinavir at 2,400 mg daily. Substitution of d4T (Zerit) at 300 mg daily for AZT was allowed. All 1,156 participants from 41 U.S. medical centers had no prior therapy with protease inhibitors and less than 1 week of therapy with 3TC. Baseline CD4 cell counts were less than or equal to 200 cells/mm3.
After a median follow-up of 38 weeks, progression to AIDS or death was 6% in the indinavir-containing arm versus 11% in the AZT (or d4T) plus 3TC arm. This 54% reduction was statistically significant. Progression to death alone was 1.4% in the indinavir arm compared to 3.1% in the AZT (or d4T) plus 3TC arm. These results were also statistically significant. CD4 cell count increases and HIV viral load reductions were greater in the indinavir-containing arm.
Participants in ACTG 320 will have an opportunity to enroll in new studies with the experimental therapies 1592 or DMP 266.
The data were presented by Scott Hammer, MD, from Harvard Medical School, at the Alta Bates 11th Annual AIDS Update for Primary Care Conference on June 6, 1997. Publication is expected soon in The New England Journal of Medicine.
Hammer S. Advances in retroviral therapies. Alta Bates 11th Annual AIDS Update for Primary Care Conference. Mills College, Oakland, CA. June 6, 1997.
Hammer SM and others. Clinical, immunological and virological outcomes in ACTG 320, a randomized, placebo-controlled trial of indinavir in combination with 2 nucleosides in HIV-1-infected persons with CD4 cell counts 200/mm3. In: Program and Abstracts from the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication. St. Petersburg, FL. June 25-28, 1997. Abstract 67.
Transmission of HIV Strain Resistant to Nevirapine and AZT
Imrie A and others. Transmission of human immunodeficiency virus type 1 resistant to nevirapine and zidovudine. Journal of Infectious Diseases 175:1502-1506. June 1997.
Ritonavir Combination Therapy Improves HIV-Related Skin Conditions
Berthelot P and others. Dramatic cutaneous psoriasis improvement in a patient with the human immunodeficiency virus treated with 2', 3'-dideoxycytidine and ritonavir. Archives of Dermatology 133:531. April 1997.
Hicks CB and others. Resolution of intractable molluscum contagiosum in a human immunodeficiency virus-infected patient after institution of antiretroviral therapy with ritonavir. Clinical Infectious Diseases 24:1023-1025. May 1997.
Ritonavir plus Saquinavir Associated with Kidney Toxicity
Witzke O and others. Side effects of ritonavir and its combination with saquinavir with special regard to renal function. AIDS 11(6):836-838. 1997.
HIV Disease Progression AIDS Progression Risk Predicted
A detailed analysis of data from 1,604 men in the Multicenter AIDS Cohort Study (MACS) has quantified 15 different hierarchical categories of risk of progression to AIDS based on a combination of baseline CD4 cell counts and HIV viral load measurements. The data represent the percentage of HIV positive individuals who will develop AIDS after 3, 6 and 9 years without combination treatment for HIV. The raw data were originally presented by John Mellors, MD, at the XI International Conference on AIDS in July 1996 and were published in the June 15, 1997 issue of Annals of Internal Medicine. A chart included in the recent Department of Health and Human Services (DHHS) guidelines for anti-HIV therapy (BETA, June 1996, page 11) shows adjusted calculations and provides additional information for physicians and patients making individual HIV treatment decisions. The researchers used the 1987 definition of AIDS, which excludes a diagnosis based on a CD4 cell count of less than 200 cells/mm3. The MACS includes only gay men and only 12% racial/ethnic minorities; no women or children are in the MACS.
The direct correlation between baseline HIV viral load levels and progression to AIDS and death has been published previously for the Pittsburgh arm of the MACS (see BETA, June 1996, pages 9-11, 41-42) and other HIV cohort groups. Now the database has been expanded to include all 4 cities of the MACS. The power of baseline HIV viral load to predict progression to AIDS and death over 10 years has been even more firmly established by the new report, since it included 1,604 men. In addition, this new report was the first to establish that higher baseline viral loads predicted a faster decline of CD4 cells counts. It also established a mathematical relationship of viral load measurements when comparing results from Chiron's Quantiplex bDNA test and Roche's Amplicor RT-PCR test.
The 1,604 men had their baseline unadjusted HIV viral loads divided into 5 hierarchical groups using the bDNA test from Chiron: (1) less than 500 copies/mL, (2) 501-3,000 copies/mL, (3) 3,001-10,000 copies/mL, (4) 10,001-30,000 copies/mL, and (5) greater than 30,000 copies/mL. The mean annual decrease in CD4 cells/mm3 for each of the 5 groups was: (1) decrease of 36 cells/mm3, (2) decrease of 45 cells/mm3, (3) decrease of 55 cells/mm3, (4) decrease of 65 cells/mm3, and (5) decrease of 76 cells/mm3. A significant relationship was shown: the higher the baseline HIV RNA level, the faster the rate of future CD4 cell decline. The authors believe that their results clearly establish that HIV blood levels are central to the pathogenesis of AIDS.
The researchers also tested blood in a subset of 400 individuals for HIV RNA viral load using both the bDNA and the RT-PCR tests. In general, the RT-PCR results were approximately 2 times greater than the bDNA results. However, at lower viral load levels (less than 10,000 copies/mL), RT-PCR results were 2.75 times higher than bDNA results. At higher viral load levels (greater than 500,000 copies/mL), RT-PCR results were only 1.57 times higher than bDNA results. Note that a 2-fold difference in viral load measurements is not statistically significant when determining the effectiveness of HIV drug therapy. The exact mathematical relationship between the 2 tests is: RT-PCR value = 5.13 x (bDNA value)0.9; and bDNA value = 0.2 x (RT-PCR value)1.1. Current guidelines from the International AIDS Society-USA and the DHHS recommend using the same test over time if possible.
Mellors J and others. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Annals of Internal Medicine126:946-954. June 15, 1997.
Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents (draft). June 1997.
Third Phase of HIV Decay Measured
The concept of potentially eradicating the virus from HIV positive persons has been proposed since the benefits of new protease inhibitor combination regimens have been realized (see BETA, September 1996, page 27). Understanding the reservoirs of HIV in the body and their various growth patterns is important when considering potential eradication. Previously, 2 phases of HIV growth and decay (fall-off) have been described. The first phase is measured in days to weeks and represents HIV production from active lymphocytes. The second phase is measured in weeks to months and represents HIV production from latently infected lymphocytes.
Now, researchers from Johns Hopkins School of Medicine have measured a hypothetical third phase of HIV decay. The half-life (length of time for 50% of an original amount to remain) is estimated at 5.7 months. This third phase of HIV decay was measured from latently infected memory CD4 cells. This measurement will help to modify the estimation of total treatment time until potential eradication may occur. Previously, this treatment duration has been estimated at 3 years. This estimate is more likely to be valid for those who start potent combination therapy shortly after HIV infection.
Finzi D and Liliciano RF. Analysis of steady state levels and decay rates of latent viral reservoirs in HIV-infected individuals. In: Program and Abstracts from the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication. St. Petersburg, Florida. June 25-28, 1997. Abstract and oral presentation 91.
Chimpanzee Develops AIDS 10 Years after HIV Infection
Novembre FJ and others. Development of AIDS in a chimpanzee infected with human immunodeficiency virus type 1. Journal of Virology 71(5):4086-4102. May 1997.
Opportunistic Infections and HIV-Related Conditions
Candidiasis
Itraconazole Solution More Effective than Capsules
Cartledge JD and others. Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidiasis. Journal of Clinical Pathology 50:477-480. 1997.
Cryptococcal Meningitis
Higher Dose of Amphotericin B More Effective than Standard Dose
Van der Horst CM and the NIAID Mycoses Study Group. Treatment of cryptococcal meningitis associated with the Acquired Immunodeficiency Syndrome. New England Journal of Medicine 337(1):15-21. July 3, 1997.
Nefopam More Effective than Meperidine in Treating Amphotericin B Side Effects
Amphotericin B used to treat cryptococcal and other deep fungal infections causes fever and severe shivering in 50-70% of patients who receive it. Hence, patients have nicknamed amphotericin B "ampho-terrible" and "shake and bake." Common pre-treatments used with amphotericin B include diphenhydramine (Benadryl), ibuprofen (Advil, Motrin), aspirin and meperidine (Demerol). Nefopam (Oxadol) is a non-narcotic analgesic that is structurally similar to both the antihistamine diphenhydramine and the anti-Parkinsonism drug orphenadrine (Norflex). Nefopam has been used effectively to treat the shivering that occurs after surgery.
Researchers from the University of Trieste in Italy compared the efficacy of nefopam to meperidine and placebo in preventing amphotericin B-induced shivering. A total of 45 patients with cancer and systemic fungal infections were enrolled. Patients were not HIV positive. The medications were administered 15 minutes before the end of a 45-minute infusion of amphotericin B. The dose of nefopam was 0.3 mg per kg and the dose of meperidine was 0.7 mg per kg.
Fifteen minutes after the amphotericin B infusion was finished, shivering occurred in only 7% of nefopam patients, compared to 40% of meperidine patients and 67% of control patients. The results were statistically significant. In 5 control patients who had persistent shivering, a dose of nefopam stopped the shivering in all in a mean time of 29 seconds. In another 5 control patients with persistent shivering, a dose of meperidine stopped the shivering in 4 of 5 in a mean time of 200 seconds. Adverse reactions to nefopam included nausea.
The authors conclude that nefopam is more effective than meperidine in preventing amphotericin B-induced shivering.
Rosa G and others. Efficacy of nefopam for the prevention and treatment of amphotericin B-induced shivering. Archives of Internal Medicine 157:1589-1592. July 28, 1997.
Cytomegalovirus Retinitis
Lack of CMV Retinitis Progression Following HAART
Before the era of highly active antiretroviral therapy (HAART) including a protease inhibitor, almost all patients treated for cytomegalovirus (CMV) retinitis would experience CMV disease progression within 2-3 weeks without prophylactic (preventive) therapy. Prophylactic therapy to prevent blindness had to be continued for life. First episode CMV retinitis has been shown to occur within 4-10 weeks after starting HAART, even after a decrease in HIV viral load and an increase in CD4 cell count (BETA, March 1997, page 30). Those cases of retinitis likely represent subclinical CMV infection present when HAART was started.
Now, researchers from the National Eye Institute at the National Institutes of Health (NIH) have reported on 3 patients who had been treated for CMV retinitis and stopped their CMV prophylactic treatment after they had a response to HAART. All of the patients' retinitis remained inactive while they took HAART for 4-7 months without CMV prophylaxis. A fourth patient developed acute CMV retinitis that stabilized and resolved after he started and responded to HAART. His retinitis has remained inactive for 12 months.
The authors caution that a larger trial of such an approach is warranted before a change in prophylaxis is undertaken by HIV patients with previously treated CMV disease. If all the CD4 cells that fight CMV are already lost before HAART is instituted, then it is possible that such an individual would still be at risk for retinitis progression and possible blindness. Conversely, preliminary research has shown that it may be possible to regrow naive CD4 cells after a certain period of HAART in some individuals. More data on this issue will be reported at the upcoming ICAAC in late September.
Whitcup SM and others. Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis. Journal of the American Medical Association 277(19):1519. May 21, 1997.
HIV-Related Dementia (Loss of Brain Function)
OPC-14117 Antioxidant Promising for HIV-Related Dementia
The Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders. Safety and tolerability of the antioxidant OPC-14117 in HIV-associated cognitive impairment. Neurology 49:142-146. July 1997.
Hepatitis A
Hepatitis A Vaccine Safe for HIV Positive Men
Bodsworth NJ and others. The effect of immunization with inactivated hepatitis A vaccine on the clinical course of HIV-1 infection: 1-year follow-up. AIDS 11:747-749. 1997.
Hepatitis C
Heterosexual Transmission of Hepatitis C is Documented
Infection with hepatitis C virus (HCV) is common among HIV positive persons. One percent of the world's 6 billion people is infected with HCV. The virus is transmitted by needle sharing, by blood transfusions before the 1990s in developed countries, from mother to newborn and sometimes by sexual contact. Liver complications due to HCV are common, including chronic hepatitis, cirrhosis, liver cancer and death. Co-infection with both HIV and HCV can accelerate the progression of either disease (see BETA, June 1997, page 53; December 1995, page 32).
Prior to this report from Italy, the exact risk of sexual transmission of HCV was not known. The study of 1,102 steady heterosexual couples with only one partner infected with HCV documented a low but significant rate of sexual transmission.
In a related story, a U.S. Public Health Service advisory committee in August recommended that anyone in the U.S. who received a blood transfusion in or before 1992 should be tested for antibodies to HCV. Approximately 290,000 people in the U.S. became infected with hepatitis C from blood transfusions before 1990. A first generation antibody test was used by U.S. blood centers in 1990, and a more specific second generation test was used starting in 1992. It is recommended that anyone who has ever shared injection drug equipment or had sex with a HCV positive person should also be tested for HCV.
Kolykhalov AA and others. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science 277:570-574. July 25, 1997.
Piazza M and others. Sexual transmission of the hepatitis C virus and efficacy of prophylaxis with intramuscular immune serum globulin. Archives of Internal Medicine 157:1537-1544. July 28, 1997.
Associated Press. Transfusions before 1992 cited as hepatitis C risk; U.S. blood advisory panel urges tests, tracing. The Washington Post: A3. August 13, 1997.
Infectious HCV Sequence is Cloned
To date, research about HCV has been hampered by a lack of an infectious molecular clone for genetic analysis and poor growth in vitro. Researchers from the University of Washington have constructed functional clones of HCV and have found that gene transcripts of the clones were infectious and able to cause hepatitis in chimpanzees. Their work has confirmed that HCV alone is able to cause disease. The researchers work will facilitate future studies of HCV growth in vitro, viral pathogenesis and variation as well as host (chimp and human) immune response.
Kolykhalov AA and others. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science 277:570-574. July 25, 1997.
Herpes Simplex
AIDS Increases Herpes Shedding
Pannuti CS and others. Asymptomatic perianal shedding of herpes simplex virus in patients with acquired immunodeficiency syndrome. Archives of Dermatology 133:180-183. February 1997.
Herpes Zoster (Shingles)
Sorivudine Effective for Herpes Zoster in People with AIDS
Painful herpes zoster skin rashes (shingles) occur over 10 times more frequently among those with HIV than among their HIV negative counterparts. Shingles outbreaks in HIV positive persons may be quite severe and can spread from the skin to other organs including the brain and eye. Shingles is caused by a reactivation of an earlier infection with varicella-zoster virus (VZV), a herpesvirus which causes chickenpox, usually during childhood. The rash starts as painful blisters in a patch or stripe distribution on one side of the body. Even after the rash has healed, pain can sometimes persist for months or longer (post-herpetic neuralgia). Recurrences of shingles are common.
The standard treatment for well-localized skin outbreaks of shingles is acyclovir (Zovirax) 800 mg orally 5 times daily for 7 days. However, the efficacy of oral acyclovir is limited by its low oral bioavailability (15-25%), dosage frequency (5 times daily) and, occasionally, by resistance to the drug. Sorivudine is a nucleoside analog with an oral bioavailability of 50-70% that has a pharmacokinetic profile that allows for once-daily dosing.
A multicenter, randomized, double-blind, acyclovir-controlled study of 125 patients from Canada, Europe, Australia and New Zealand was reported in the July issue of the Journal of Infectious Diseases. All patients were HIV positive and were enrolled if they arrived at their provider's office within 72 hours of developing a shingles rash. Blister fluid was cultured for VZV. Patients were randomized to receive 10 days of either sorivudine at 40 mg once daily or acyclovir at 800 mg 5 times daily. The sorivudine group was also given acyclovir placebo tablets 5 times daily, while the acyclovir group was also given sorivudine placebo tablets once daily. The mean CD4 cell count was 244 cells/mm3 in the sorivudine arm and 214 cells/mm3 in the acyclovir arm.
The study was terminated early because one arm demonstrated a significant difference in time until new blister formation stopped. Unblinding of the study indicated that those on the sorivudine arm had no new blister formation after 3 days of taking the drug, while the same endpoint in the acyclovir arm occurred after 4 days. This probably reflects sorivudine's superior ability to block new virus production. The significance of the shorter duration until no new blistering occurred still held whether the patient started sorivudine less than 48 hours or between 48-72 hours after the rash started. The sorivudine group had a median time of 8 days until all sores were 100% crusted (normal progression towards healing), compared with 9 days for the acyclovir group. These results also differed significantly. There was no difference between the 2 groups in terms of median time until complete healing (21 days for both).
In the 12 months after the initial shingles rash was healed, persons in the sorivudine arm demonstrated a significantly lower rate of recurrent episodes of shingles (11%) compared to the acyclovir arm (26%). This represents a 58% reduction for the sorivudine arm. No enrollee discontinued the drug due to adverse events or laboratory abnormalities. A total of 10 deaths occurred due to other AIDS-related illnesses, 3 in the sorivudine arm and 7 in the acyclovir arm. No deaths occurred due to sorivudine.
Sorivudine is a promising new antiviral therapy for HIV-related localized VZV skin infection. For acyclovir-resistant herpes zoster, intravenous foscarnet (Foscavir) has demonstrated benefits; however, this regimen is not FDA-approved. Two newer drugs — valacyclovir (Valtrex) and famciclovir (Famvir) — that are FDA-approved for herpes zoster infection in HIV negative persons are not FDA-approved for HIV positive persons.
Abramowicz M, ed. Drugs for non-HIV viral infections. The Medical Letter on Drugs and Therapeutics 39(1006):69-76. August 1, 1997.
Bodsworth NJ and others. Evaluation of sorivudine (BV-araU) versus acyclovir in the treatment of acute localized herpes zoster in human immunodeficiency virus-infected adults. Journal of Infectious Diseases 176:103-111. July 1997.
Kaposi's Sarcoma
Low-Dose Paclitaxel Effective in Advanced KS
Paclitaxel (Taxol) is a chemotherapeutic agent derived from the bark of yew trees. It is FDA-approved for breast and ovarian cancer. A recent study presented at the National AIDS and Malignancy Conference revealed that low-dose paclitaxel has benefits for severe AIDS-related Kaposi's sarcoma (KS). Fifty-six adult patients, including 2 women, were enrolled in the study. All had more than 25 KS lesions on the skin or mucous membranes, KS in internal organs (45%) or KS-related swelling (70%). Seventy-one percent of participants had previously received treatment for KS. A prior AIDS-defining illness was reported by 75% of the enrollees. The median baseline CD4 cell count was 20 cells/mm3.
In spite of previous reports of an effective dose of paclitaxel for KS of 135 mg per square meter every 3 weeks, the current study used a lower dose of 100 mg per square meter every 2 weeks. To help prevent side effects from the infusion, all patients were pretreated with dexamethasone (Decadron), cimetidine (Tagamet) and diphenhydramine (Benadryl). Patients were permitted to continue anti-HIV therapy. The median number of treatments was 10. An interim analysis was conducted at approximately 70 weeks.
The results revealed 1 patient (2%) with a complete response and 32 patients (57%) with a partial response. A partial response included a reduction in size or volume of KS lesions. Swelling decreased in 79% of patients. The median time to onset of response to therapy was 6.1 weeks. Response lasted a median of 10.4 months.
The most common serious side effect was a moderate-to-severe low white blood cell count (neutropenia), occurring in 62% of participants. Low red blood cell count (anemia) occurred in 25%, while low blood platelet count occurred in 27%. Other severe non-blood-related adverse effects were uncommon at 15%.
Based on this report, the authors recommended a randomized trial. The FDA Oncology Drugs Advisory Committee recommended in June that paclitaxel be approved as a second-line drug for AIDS-related KS. Full FDA approval will make recruiting a randomized trial more difficult. FDA approval of paclitaxel will add to the number of drugs approved to treat KS. A marked improvement and even resolution of KS has been reported by those using highly active antiretroviral therapy, even without specific therapy for KS (see BETA, March 1997, page 29).
Gill PS and others. Low dose paclitaxel (Taxol) is highly effective in the treatment of patients with advanced AIDS-related Kaposi's sarcoma. Program and Abstracts of the National AIDS Malignancy Conference; Bethesda, Maryland. April 28-30, 1997. Abstract 75. Also Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 14(4):A1-A54. April 1997.
KS and Herpesviruses
Kempf W and others. CD68 cells of monocyte/macrophage lineage in the environment of AIDS-associated and classic-sporadic Kaposi's sarcoma are singly or doubly infected with human herpesviruses 7 and 6B. Proceedings of the National Academy of Sciences 94:7600-7605. July 1997.
Takahashi K and others. Selective activity of various nucleoside and nucleotide analogues against human herpesvirus 6 and 7. Antiviral Chemistry and Chemotherapy 81(1):24-31. 1997.
Rettig MB and others. Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients. Science 276:1851-1854. June 1997.
Microsporidiosis (Diarrhea)
Thalidomide Shows Benefit for Microsporidial Diarrhea
Chronic diarrhea is a common symptom in HIV positive persons (see BETA, June 1997, pages 28-32, 58). Microsporidia is the most common infectious cause of diarrhea among patients referred to gastroenterologists. Over 90% of microsporidia infections are due to Enterocytozoon bieneusi, which is difficult to treat. Albendazole (Valbazen) and metronidazole (Flagyl) may reduce the volume of diarrhea, but the infection is not cleared and relapse is quite common.
Thalidomide (Synovir) is an experimental drug with efficacy for oral aphthous ulcers and wasting syndrome. The FDA banned the drug in the U.S. in the 1960s due to fetal abnormalities among newborns whose mothers who took the drug during pregnancy. Researchers from Charing Cross and Westminster Medical School in London have reported that thalidomide can treat some E.bieneusi diarrhea.
The authors had previously reported that tumor necrosis factor-alpha (TNF-alpha) levels were elevated in the stools of HIV positive persons with microsporidial diarrhea. Thalidomide is a known inhibitor of TNF-alpha, so a trial seemed appropriate.
Eighteen HIV positive patients with diarrhea due to E. bieneusi were enrolled. None had responded to albendazole therapy. The patients were given thalidomide doses of 100 mg orally at bedtime for 1 month. Thirty-eight percent of these patients achieved complete clinical remission including cessation of diarrhea, significant weight gain and improved intestinal biopsies. Even though the organism was not eradicated on biopsy, abnormal forms and shapes of the organism were found. Another 17% of patients achieved partial remission, including a reduction in the frequency and weight of daily diarrhea. Another 45% derived no benefit from the drug.
There was a significant decrease in daily stool frequencies from 5.3 to 3.1. Body weight increased significantly by 1.2 kg. Stool levels of TNF-alpha decreased by half, but this result was not statistically significant.
The dosage of thalidomide for 2 patients was decreased to 50 mg due to daytime drowsiness. Four patients experienced an itchy rash due to the drug, which was treated with antihistamines. No other adverse event occurred, including peripheral neuropathy. Follow-up of the patients after the 1-month treatment period was not mentioned in the report, so it is not known whether those who responded later relapsed.
Since the study period was completed in June 1995, it is possible that HAART may have decreased the incidence of diarrhea due to microsporidia. HAART has shown benefits for those with cryptosporidial diarrhea and wasting syndrome (see BETA, March 1997, page 29). Women of childbearing age would need to avoid pregnancy while taking thalidomide to prevent severe deformities in their newborns.
Sharpstone D and others. Thalidomide: a novel therapy for microsporidiosis. Gastroenterology 112:1823-1829. June 1997.
Furazolidone Shows Benefits for Microsporidial Diarrhea
Dionisio D and others. Enterocytozoon bieneusi in AIDS: symptomatic relief and parasite changes after furazolidone. Journal of Clinical Pathology 50:472-476. 1997.
Myopathy (Muscle Disease)
Selenium Deficiency Documented in People with HIV with Muscle Aches and Weakness
Chariot P and others. Muscle involvement in human immunodeficiency virus-infected patients is associated with marked selenium deficiency. Muscle and Nerve 20:386-389. March 1997.
Pneumocystis carinii Pneumonia
U.S. Public Health Service Recommends Maintaining PCP Prophylaxis
The era of HAART has raised the question as to whether preventive antibiotics can be safely stopped after CD4 cell counts increase over specified levels. For the treatment of life-threatening Pneumocystis carinii pneumonia (PCP) in the pre-HAART era, antibiotics were recommended after the CD4 cell count decreased below 200 cells/mm3. HAART increases the CD4 cell count over that threshold in a significant percentage of those who respond to therapy. Can people with HIV stop their PCP prophylaxis and not risk PCP recurrence if their CD4 cell counts increase to greater than 200 cells/mm3?
Most clinicians feel that stopping PCP prophylaxis in this situation would be too risky. Physicians from the U.S. Public Health Service agree. In a letter to the editor of the American Journal of Respiratory and Critical Care Medicine, Abe Macher, MD, and Eric Goosby, MD, cautioned clinicians and patients not to stop PCP prophylaxis, even if the CD4 cell count increases to greater than 200 cells/mm3. The reason is that once the CD4 cells designated to respond to PCP are lost, they might not return, even after HAART increases the total number of CD4 cells. Also, the number of naive CD4 cells (cells that respond to infection with new organisms) continues to decline with progressive HIV disease. It is likely that in the near future research will determine whether subsets of patients who respond to HAART may be able to safely discontinue PCP and/or Mycobacterium avium complex (MAC) prophylaxis.
Macher AM and Goosby EP. Maintenance of chemoprophylaxis against Pneumocystis carinii despite combination antiretroviral treatment associated CD4+ T-lymphocytosis. American Journal of Respiratory and Critical Care Medicine 155(4):1490. 1997.
Syphilis
Standard Syphilis Treatment Adequate for HIV Positive Persons
Since the early years of the HIV/AIDS epidemic, there has been controversy over whether HIV positive persons with syphilis need more aggressive therapy than their HIV negative counterparts. Syphilis is a common sexually-transmitted disease (STD) in people with HIV/AIDS. It can be transmitted sexually, through needle-sharing and from mother to newborn. Some untreated syphilis patients progress to brain involvement. A report from the Syphilis and HIV Study Group, affiliated with the Centers for Disease Control and Prevention (CDC), was published in the July 31, 1997 issue of The New England Journal of Medicine.
The treatment recommended by the CDC for early syphilis is penicillin G benzathine (Bicillin) injection. However, this treatment does not allow for adequate treatment of syphilis organisms in the cerebrospinal fluid (CSF) around the brain and spinal cord. Prior to this study, some HIV positive persons with early syphilis who had received recommended penicillin therapy still had detectable organisms in their CSF. This was believed to be associated with underlying immunodeficiency due to HIV. To treat syphilis in the CSF, physicians normally added amoxicillin and probenecid to therapy.
A multicenter, randomized, double-blind trial of 541 patients with early syphilis included 101 (18%) with HIV infection. The 2 treatment arms received 2.4 million units of penicillin G benzathine by intramuscular injection, with or without 2 grams of amoxicillin plus 500 mg probenecid, each orally 3 times daily for 10 days. Those not assigned to supplemental amoxicillin plus probenecid were given placebo pills instead. Participants were followed for up to 1 year.
Results showed that the rates of clearance of syphilis sores (chancres) and rashes did not differ significantly by treatment group or by HIV status. Six months after therapy, treatment failure, defined by standard blood testing, was 18% in the penicillin group and 17% in the 3-drug group. The patient who failed therapy because of a new syphilis skin rash ("clinical failure") was HIV positive and had received penicillin monotherapy. Syphilis was detected in the CSF in 24% before treatment and 20% of those tested after treatment. HIV status did not affect the rates of detection of syphilis-causing organisms in the CSF either before or after treatment.
There were several limitations to the study. First, the 1-year follow-up rate was only 52%. Second, only 51% of participants indicated that they took all prescribed pills. Third, 12% indicated at the 6-month mark that they had taken other prescribed antibiotics (outside the study) with known efficacy against syphilis. However, HIV positive patients did not differ significantly from HIV negative ones with regard to follow-up rate, compliance or receipt of outside antibiotics. The 2 different treatment groups also did not differ significantly in these areas. The authors note that "…we cannot rule out the infrequent occurrence of serious adverse clinical outcomes in HIV-infected patients after (standard) treatment for syphilis."
This reviewer found the article's conclusions surprisingly weak and the authors' usage of the term "adequate" to be nothing short of inadequate. A 20-25% rate of syphilis detection in the CSF before and after therapy and a 17-18% failure rate in both therapy arms should not suggest that the current standard penicillin therapy is "adequate." These results indicate that further studies using other antibiotic regimens and combinations should be pursued. This may be somewhat difficult, given the decreasing incidence of syphilis in the U.S. and in other developed countries. Also, since the study was performed before the era of HAART, results might be somewhat different if the study were to be repeated today. In the meantime, for HIV positive people, CSF evaluation as a part of diagnosing early syphilis, along with close follow-up for assessing treatment success, is very important. Many experienced HIV/AIDS physicians would choose more aggressive therapy than that recommended in the CDC guidelines for treating early syphilis among HIV positive people, particularly for those not receiving HAART.
Rolfs RT and others. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. New England Journal of Medicine 337:307-314. July 31, 1997.
Tuberculosis
Interferon-Gamma Blood Test may be Better than Skin Test for Detecting TB
The standard for detecting past or current infection with tuberculosis (TB) has been a skin test called purified protein derivative (PPD). A few drops of killed TB protein fluid is injected as a "bubble" within the skin. After 48-72 hours, the skin is then examined by a healthcare provider. A skin lump size of 1 cm or greater in HIV negative persons or 0.5 cm or greater in HIV pos-itive persons is considered "positive," indicating past or current TB infection. Because of waning immune function associated with progressive HIV disease, many HIV positive persons are unable to form a reactive skin lump even if they have been ex-posed to TB, a condition known as anergy. This "false negative" skin test result sometimes makes diagnosing TB infection difficult.
Researchers from Johns Hopkins School of Medicine have reported using a blood test in injection drug users to detect past exposure to TB. The new blood test uses the same TB proteins used in the skin test. Measurements are made of blood levels of interferon-gamma (IFN-gamma) that reacts with TB proteins.
The investigators found that blood IFN-gamma levels correlated 89-100% with the results of PPD skin tests in the same person, regardless of HIV status. However, some individuals who were PPD skin test-negative had IFN-gamma reactivity to TB protein in their blood (some of these were known to have had prior positive PPD skin tests). The authors believe that these individuals truly had past TB infection and that the negative skin test results were "false negatives." Moreover, some HIV positive patients with immune anergy had positive IFN-gamma blood tests for TB protein. Again, the authors believe that some of the anergic patients truly had past TB infection with "false negative" skin test results.
The amount of IFN-gamma secreted in the blood test correlated with the skin lump size, suggesting a dose-response relationship. In addition, the blood test can differentiate between infections due to Mycobacterium tuberculosis and those due to Mycobacterium avium complex (MAC), another major life-threatening infection in people with AIDS. Another positive feature is the blood test's ability to distinguish between past TB infection and past vaccination with Bacille Calmette-Guérin (BCG), a type of TB vaccine used in countries with high rates of TB to help prevent the more severe manifestations of tuberculosis.
The authors note that the best feature of the blood test is that people do not need to return to a clinic 2-3 days after a skin test injection for skin test reading. Without inducements, the return rate for skin test reading approaches 35%. Even with food voucher inducements, return rates reach only 60%. In the current study, financial inducements led to a return rate of greater than 95%.
Converse PJ and others. Comparison of a tuberculin interferon-gamma assay with the tuberculin skin test in high-risk adults: effect of human immunodeficiency virus infection. Journal of Infectious Diseases 176:144-150. July 1997.
No Benefit of Isoniazid Prophylaxis in HIV Positive Persons with Anergy
Mycobacterial tuberculosis infection is a significant threat to both HIV positive and HIV negative persons. As a measure to prevent further spread of TB in the U.S., the CDC recommended in 1991 that HIV positive persons at "high risk for TB" who have immune anergy take 12 months of isoniazid therapy. A state of "high risk for TB" exists when the local prevalence of TB is greater than or equal to 10%. Such conditions exist among people from countries with high TB rates (for example parts of Asia and Africa), certain inner city populations, homeless persons, drug or alcohol abusers, and residents of long-term care and correctional facilities. Researchers from the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) attempted to determine the potential benefits of the 1991 CDC recommendation. The report appears in the July 31, 1997 issue of The New England Journal of Medicine.
The multicenter, randomized, double-blind, placebo-controlled trial enrolled 517 patients from 8 U.S. geographical areas including San Francisco. Over 75% of participants were from New York City. Injection drug users comprised 58%, and 32% were women. African-Americans comprised 47%, while 33% were Latino. Over 90% of the enrollees had 2 or more risk factors for TB exposure. The 3 skin tests used were PPD, mumps antigen and tetanus antigen.
The researchers chose to treat using only 6 months of isoniazid therapy to minimize potential toxic side effects among participants who were not infected with TB. After 33 months of follow-up, the results showed that there were no significant differences between the isoniazid and placebo groups in rate of developing tuberculosis, progression of HIV disease or death, or adverse events due to isoniazid. Even though active TB developed in only 6 of 257 (2.3%) of placebo patients and 3 of 260 (1.2%) of isoniazid-treated patients, the results were statistically insignificant. Death rates in both groups were identical at 49%, and were often due to AIDS-related causes. No patient in the study died due to TB.
The authors note that the study took place when TB control efforts had expanded significantly in the U.S., particularly in New York City. Those efforts have been associated with decreasing TB rates in the U.S.
The authors concluded that their study indicated that the use of isoniazid prophylaxis is not supported for HIV positive persons at high risk for TB with anergy unless they have been exposed to active TB. Limitations of the study include a 6-7% rate of participants who were lost to follow-up (similar in both isoniazid and placebo groups) and only a 63% rate of participants who completed 6 months of treatment.
Gordin FM and others. A controlled trial of isoniazid in persons with anergy and human immunodeficiency virus infection who are at high risk for tuberculosis. New England Journal of Medicine 337:315-320. July 31, 1997.
Wasting Syndrome
HIV-Related Weight Loss is Comprised of Fat and Muscle
Mulligan K and others. Cross-sectional and longitudinal evaluation of body composition in men with HIV infection. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 15(1):43-48. 1997.
HIV Transmission
Possible HIV Transmission by Deep Kissing Associated with Blood
In July, CDC reported a possible case of HIV transmission via the oral route, associated with saliva contaminated with blood from bleeding gums. The heterosexual couple in this case is from the San Francisco Bay Area and was a part of a heterosexual HIV transmission study in which one partner was HIV positive and the other was HIV negative.
The initially HIV-infected man was an injection drug user with poor oral hygiene and gingivitis (gum infection) associated with bleeding. The man indicated that his gums frequently bled after brushing and flossing his teeth. The couple indicated that they generally had sexual intercourse including "deep kissing" when they went to bed, after he had brushed and flossed his teeth.
In July 1994, his female partner was HIV negative according to enzyme immunoassay and PCR tests. Starting on August 26, 1994, she had an 7-10 day illness consistent with acute (primary) HIV infection, including fever, sore throat, swollen lymph nodes and sore muscles. She tested HIV positive in July and September 1995. The woman denied any other illnesses from July 1994 to July 1995. During the 13 months before her first positive HIV test, she denied any risk factors for HIV transmission except sexual contact with her HIV positive male partner.
From June 1994 until July 1995, the couple indicated that they had penile-vaginal intercourse approximately 6 times monthly, yet never while she was menstruating. They both indicated that they always used a condom during vaginal intercourse, usually with the spermicide nonoxynol 9. They denied any condom breakage during that time period, and believed that the condom remained on his penis each time it was withdrawn. The couple engaged in French ("deep," open-mouth) kissing several times monthly. The couple indicated that they engaged in oral sex "occasionally," but never exchanged semen or blood. The couple denied engaging in anal intercourse during the 13-month interval. The woman did recall using her partner's razor and toothbrush, once each, with no visible blood on either.
During 2 medical visits in April-May 1995, the man's mouth was found to have gingivitis, canker sores and oral hairy leukoplakia. In August 1994, he had a normal blood platelet cell count (if the count is low, easy bruising or bleeding may occur). His CD4 count at that time was 110 cells/mm3.
The woman had oral endodontic surgery ("root canal") on August 8, 1994, 18 days before the onset of her acute HIV illness. Her dental examination prior to surgery indicated poor gum health, periodontitis (gum disease and deterioration) and poor dental hygiene. The dentist tested HIV negative in May 1996.
In April 1996, detailed analysis of each of the partner's HIV genetic material indicated only a 1.6% difference. CDC concluded that such a high degree of relatedness strongly suggested that HIV was transmitted from one to the other.
In an editorial comment, the CDC stated, "Athough the exact route of transmission in this report cannot be determined, the most likely possibility is that the woman became infected through mucous membrane exposure to the man's saliva that was contaminated by blood from his bleeding gums or exudate [body fluid] from undetected oral lesions. Such exposure may have occurred during ‘deep kissing'; the woman's inflamed gingival mucosa [gums] might have been a contributing factor."
In the absence of blood, oral fluids, including saliva, have specific components that inactivate HIV. Such fluids rarely, if ever, have been found to contain infectious HIV. Several studies have shown this, including one just published in the journal AIDS. There have been 2 reports in the medical literature of HIV transmission by human bites when saliva was contaminated with blood.
This report underscores a problem encountered by sex partners when one is HIV infected and the other is not. Meticulous care must be taken by both partners to practice safer sex. This would include regular dental care to prevent mouth and gum disease, and avoiding tooth brushing and flossing before sexual activity. The sharing of toothbrushes and razors should also be avoided.
Transmission of HIV possibly associated with exposure of mucous membrane to contaminated blood. Morbidity and Mortality Weekly Report 46(27):620-623. July 11, 1997.
Chebbi F and others. Search for infectious HIV in gingival crevicular fluid and saliva of advanced AIDS patients with severe periodontitis. AIDS 11:927-928. 1997.
Vaginal Bleeding after Intercourse is a Documented Risk Factor for Heterosexual Transmission of HIV to Women
Guimaraes MDC and others. Postcoital vaginal bleeding as a risk factor for transmission of the human immunodeficiency virus in a heterosexual partner study in Brazil. Archives of Internal Medicine 157:1362-1368. June 23, 1997.
Increased Perinatal Transmission among Injecting Mothers
Bulterys M and others. Sexual behavior and injection drug use during pregnancy and vertical transmission of HIV-1. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 15(1):76-81. May 1, 1997.
Matheson PB and others. Association of maternal drug use during pregnancy with mother-to-child HIV transmission. AIDS 11(7):941-942. 1997.
Increased Perinatal HIV Transmission when Mother is also Hepatitis C Virus Positive
Hershow RC and others. Increased vertical transmission of human immunodeficiency virus from hepatitis C virus-coinfected mothers. Journal of Infectious Diseases 176:414-420. August 1997.
HIV Transmission from Bisexual Men to Women
Kahn JG and others. How many HIV infections cross the bisexual bridge? An estimate from the United States. AIDS 11(8):1031-1037. 1997.
HIV Positive Gay Men Have 2-Fold Higher Risk of Urethritis Due to Gonorrhea
Lafferty WE and others. Sexually transmitted diseases in men who have sex with men: acquisition of gonorrhea and nongonococcal urethritis by fellatio and implications for STD/HIV prevention. Sexually Transmitted Diseases 24(5):272-278. May 1997.
Harvey S. Bartnof, MD, has been a member of the Scientific Advisory Committee at the San Francisco AIDS Foundation since 1987.
This information is designed to support, not replace, the relationship that exists between you and your doctor.