Published in the Bulletin of Experimental Treatments for AIDS January 1999 issue, by the San Francisco AIDS Foundation.

-- Main Page
-- Top Conference Stories
-- Treatment Guidelines and Immune-Based Therapies
-- Protease Inhibitor Complications And Side Effects
-- HIV Viral Load, Resistance Testing, and Adherence
-- Anti-HIV Drugs And Combinations
-- Opportunistic And Other Conditions
-- Women And Pregnancy, Miscellaneous

January 1999 Table of Contents

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Highlights from Recent Conferences -- Opportunistic And Other Conditions

Harvey S. Bartnof, MD

1263W94 Reduces Semen CMV Levels

• The experimental drug 1263W94 significantly decreases cytomegalovirus (CMV) levels in semen
• In a Phase I/II study of 24 men, doses were 100, 200, or 400 mg three times daily, or 600 mg twice daily.
• Reported adverse events were fatigue, headache, nausea, and taste disturbances.

Maintenance Fomivirsen Eye Injections

• Monthly maintenance eye injections of fomivirsen (Vitravene) are effective for resistant CMV retinitis (for background on fomivirsen, see BETA, April 1998).
• 270 eyes were treated
• The dose used was 330 micrograms; induction treatment was either weekly for three weeks or every other week for two doses.
• Side effects, including eye inflammation and increased eye pressure, were usually transient and treatable.
• The discontinuation rates due to side effects was 12-18%.

Meenken, C. and others. Advantages of a new local therapy, fomivirsen, for the treatment of CMV retinitis. 4th ICDTHI. Abstract P269.

Treatment Recommended for Persons with Positive CMV Blood Antigen Tests

• Researchers recommend CMV treatment for people with AIDS who have positive CMV blood antigen tests, even if they do not have retinal disease or symptoms.
• Positive CMV antigen tests predicted future CMV eye disease and earlier death, even when statistically corrected for CD4 count.

Carton, J.A. and others. Value of cytomegalovirus detection by antigenemia assay on disease development and survival in AIDS patients. 38th ICAAC. Abstract H-21

Ganciclovir Resistance

• Preventive oral ganciclovir therapy for CMV leads to resistance in 23% after one year

Smith, L.L. and others. Development of resistant cytomegalovirus genotypes during oral ganciclovir prophylaxis/preemptive therapy. 38th ICAAC. Abstract H-120.

Reactivation of HBV and HCV with HAART

• Protease inhibitor-containing HAART can cause a reactivation of hepatitis B virus (HBV) and, less commonly, hepatitis C virus (HCV).
• Increases in CD4 cell counts and decreases in HIV viral loads were seen.
• 30-40% of HIV positive persons in the U.S. are also infected with HCV.

Several poster presentations at both ICAAC and IDSA concerned HAART-induced increases in liver enzyme levels and/or reactivation of HBV or HCV. In the first study, by the CDC, 102 patients started on protease inhibitor-containing HAART were examined for changes in liver enzyme levels. Despite increases in CD4 cell counts and decreases in HIV viral load, the mean level of aspartate aminotransferase (AST, a liver enzyme) significantly doubled in the 20 patients with HBV (measured by the presence of surface antigen). Among the 31 patients positive for HCV, AST levels remained unchanged. Among the 51 patients who were negative for both HBV and HCV, there were also no significant changes in AST levels.

In a second report from Ealing Hospital in London, researchers reviewed the charts of eight patients out of 200 who had increased liver enzymes and liver disease after HAART was started. Seven required hospitalization and six required liver biopsy. The results showed that one person had a worsening of chronic hepatitis B, while two others had an exacerbation of chronic hepatitis C. Another person experienced acute hepatitis A. In three of those four, HAART was continued with a gradual improvement in liver enzyme levels and liver disease symptoms. In another two cases, HAART itself was deemed to be the cause of liver disease without underlying viral liver infection. HAART was discontinued and the liver abnormalities resolved. Protease-sparing anti-HIV regimens (see BETA, October 1998) were then successfully instituted without adverse effects on the liver.

A third poster, authored by researchers at Baylor College of Medicine, found that liver dysfunction in persons co-infected with HIV and HCV was not affected by protease inhibitors. There were 142 people in this study. The researchers found that liver disease due to HCV occurred independently of HIV viral load and at all CD4 counts greater than 50 cells/mm³.

A fourth poster was a case report of severe exacerbation of hepatitis B after HAART was started in a person initially positive for HIV, HBV, and HCV. The person's HAART regimen included ritonavir, indinavir, and AZT. One month after starting therapy, the person was hospitalized due to severe liver disease with jaundice (yellowing of the skin and eyes). His bilirubin (bile pigment) level was high at 190 µm/L, while his alanine aminotransferase (ALT, another liver enzyme) level was 40 times his baseline normal level. The person's blood showed reactivation (or possibly superinfection with a second strain) of HBV; surface antigen, IgM antibody, and HBV DNA tests all became positive. At the same time, his HCV tests remained unchanged. Other new infections were not present. After stopping HAART, there was a gradual, four-week normalization of blood tests and a resolution of symptoms. The likely cause of the hepatitis B reactivation was HAART-induced improvement in the person's immune response.

Sulkowski, M.S. and others. Hepatotoxicity associated with antiretroviral therapy among HIV-infected adults: the role of protease inhibitors and hepatitis C infection. 38th ICAAC. Abstract H-116.

Decrease in HCV Viral Load After HAART

• After three months of HAART, HCV RNA levels had doubled.
• After one year of HAART, HCV levels were half of baseline levels.
• The study included 30 patients co-infected with HIV and HCV from Spain; all patients showed HAART-induced decreases in HIV viral load and increases in CD4 counts.
• Most other studies have shown no benefits of HAART for hepatitis C.

Verdon, R. and others HIV-HCV coinfection: is HIV viral load decrease associated with HCV viral load variations. 38th ICAAC. Abstract H-111.

Fluorocytidine Active Against HIV and HBV

• Fluorocytidine (FTC) shows activity against both HIV and HBV.
• A once-daily dose of 200 mg reduced HIV viral load by 1.9 log copies/mL.

Wang, L.H. and others. FTC: a potent and selective anti-HIV and anti-HBV agent demonstrating desirable pharmacokinetic characteristics. 36th IDSA. Abstract 415Fr.

Hepatitis A Vaccine Recommended for HIV Positive Injection Drug Users

• Hepatitis A vaccine is recommended for injection drug users who are HIV positive and hepatitis A virus (HAV) negative.

While rarely lethal, acute hepatitis A has been known to lead to death in carriers of HCV. HIV positive injection drug users have high rates of both HBV and HCV. Even though the newly available vaccine for hepatitis A has been recommended for all persons "at risk for HIV," its use in the HIV positive population has been low. Researchers from the Veterans' Administration Hospital in Richmond, Virginia, have issued additional specific recommendations regarding the vaccine. They found that among 140 HIV positive patients in their clinic, there were high rates of hepatitis A and hepatitis C among those with a history of injection drug use. Due to the potential lethality of hepatitis A in carriers of HCV, the researchers state that all HIV positive injection drug users should be screened for antibodies to HAV. Those who are HAV negative should receive the hepatitis A vaccine. This reviewer finds the recommendations somewhat limited, and believes that the hepatitis A vaccine should be given to all HIV positive people who have a negative test for HAV antibodies.

Orenstein, R. and others. Hepatitis A seroprevalence in the HIV-infected population: implication for vaccine strategies. 36th IDSA. Abstract 411Fr.

More Evidence of HCV Sexual Transmission

• More evidence has been presented that indicates that HCV is transmitted by heterosexual sex.

While the primary mode of HCV transmission is percutaneous exposure (for example, through shared injection equipment or blood transfusions prior to 1992), sexual transmission does occur at a low rate (see "Hepatitis," BETA, January 1998). Now, researchers from the CDC have found more evidence of heterosexual sexual transmission of HCV. A total of 534 female sex workers from eight urban locations were enrolled in a study in 1986-1987. Women who reported a history of injection drug use and those who had evidence of needle track marks were excluded. HCV infection was found in 12%.

The results indicated that sexual practices involving injury or trauma (bleeding, biting, or piercing), no condom use in the past five years, and a higher number of lifetime, paying male sex partners were significantly associated with a higher rate of HCV infection. Another association was past infection with HBV, which is transmitted similarly to HIV. Interestingly, there was no statistical association between HCV infection and being HIV positive.

The authors conclude that their study has found additional evidence for heterosexual transmission of HCV. Also, bleeding or trauma associated with sexual practices increases the risk of infection, and consistent use of condoms would be expected to decrease the risk.

Williams, C.L. and others. Risk factors for sexual transmission of hepatitis C virus among non-injecting-drug-using female prostitutes in the United States. 36th IDSA. Abstract 24.

AIDS-Related Dementia and Alzheimer's Share Same Gene

• A gene mutation associated with a higher risk of Alzheimer’s disease is also linked to HIV-related dementia.

One of the most feared consequences of HIV is AIDS-related dementia. This condition manifests as progressive loss of specific brain function, including memory. Now, researchers have determined that the same genetic mutation that increases the risk for Alzheimer’s dementia in HIV negative elderly persons may place HIV positive persons at higher risk for AIDS-related dementia (AIDS dementia complex) and peripheral neuropathy.

Researchers from the U.S., Denmark, and Sweden looked for a gene linked to Alzheimer’s disease, called the epsilon-4 mutation of apolipoprotein E, in 44 men with HIV infection. Then the men were tested for dementia regularly for five years. Eleven of the 44 (25%) had the mutation, while the remainder did not. After only three years, the proportion of those with the mutation who had dementia was twice as high as the proportion in the group without the mutation. Also, the men without the mutation also had less peripheral neuropathy. After controlling for CD4 count, the mutation had an even greater effect on nervous system abnormalities.

The results suggest that genetic factors may increase the risk of dementia and neuropathy. Larger trials are needed to confirm these results.

Corder, E. and others. HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nature Medicine 4(10): 1182-1884. October 1998.

HPV Shedding in People with AIDS

• A majority (79%) of people with advanced AIDS have perianal (around the anus) shedding of human papillomavirus (HPV) DNA; HPV is known to cause warts.
• Shedding occurs even in people without symptoms of warts or a history of receptive anal intercourse.
• The study included 72 patients (25% female) from São Paulo, Brazil who did not have perianal lesions.

Levi, J.E. and others. Asymptomatic HPV/DNA shedding from perianal region of AIDS patients. 38th ICAAC. Abstract H-26.

Influenza Vaccine

• The influenza vaccine is recommended for all persons with HIV.

While the majority of HIV negative persons recover from influenza virus infection ("flu") every winter, several tens of thousands of persons in the U.S. die every year from flu complications, usually pneumonia (lung infection). Most of those who die are elderly or have chronic diseases. Rates of influenza-related pneumonia have not been described in HIV positive persons taking HAART.

Researchers from the University of Massachusetts reported on six HIV positive persons who contracted pneumonia following influenza during the 1997-1998 winter season. Four required hospitalization due to low blood oxygen levels accompanied by cough and fever. Three of the four were taking anti-HIV therapy, and three of the four had received a flu vaccination. Two had an HIV viral load of 150 copies/mL or less; the third had only 1,000 copies/mL. Three of the four had a CD4 count greater than 200 cells/mm³. Two of the patients received rimantadine (Flumadine); this antiviral medication can help decrease flu symptoms if taken early in infection. All four recovered after a hospitalization of six to seven days.

The report indicates that life-threatening pneumonia can complicate influenza in HIV positive persons who have had a good response to HAART. The influenza vaccine can be quite helpful in preventing or mitigating flu symptoms. The vaccine is recommended for all persons with HIV. It is still not too late to get the vaccine for this winter season!

Radwan, H. and other. Severe influenza pneumonia in HIV patients during 1997-1998 influenza season. 36th IDSA. Abstract 305Sa.

Berberine plus Albendazole for Microsporidiosis

• Berberine plus albendazole has a synergistic (enhanced) effect against microsporidiosis compared to either drug alone in an animal model.
• Microsporidiosis is a parasitic disease that can cause diarrhea.

McDevitt, J.T. and others. Combined effectiveness of berberine and albendazole against microsporidia. 38th ICAAC. Abstract F-188.

New Drugs Show Efficacy Against MAC

• Intravenous liposomal amikacin (MiKasome) is shown to have efficacy against Mycobacterium avium complex (MAC); once weekly dosing is possible.
• Mefloquin, an FDA-approved anti-malaria drug, shows activity against MAC in an animal model.
• Arbekacin plus ethambutol is more effective than clarithromycin plus ethambutol in an in vitro model.
• Linezolid, an oxazoladinine class drug, also shows benefits in vitro.

Wu, M. and others. Linezolid, a new oxazoladinine, has activity in vitro and in macrophage culture system against Mycobacterium avium complex (MAC). 38th ICAAC. Abstract E-143

Neither Acupuncture Nor Amitriptyline are Beneficial for Peripheral Neuropathy

• A placebo-controlled trial showed no significant benefits of acupuncture or amitriptyline compared to placebo for peripheral neuropathy.

Peripheral sensory neuropathy is a troubling condition that occurs in approximately one-third of HIV positive persons. Symptoms include numbness, tingling, and burning in the feet and sometimes the hands ("stocking and glove" distribution). Certain anti-HIV drugs can cause the symptoms, including ddI, ddC, and d4T. In the absence of other associated causes, treatments include narcotic and non-narcotic pain medications, antidepressant drugs, anticonvulsants, and acupuncture. The use of these treatments has been based on anecdotal case reports or on the results of studies of neuropathy associated with other diseases.

Since there had not been a large, multicenter, double-blind, placebo-controlled study of the various treatments, researchers from of Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) attempted to conduct one. A total of 250 HIV positive persons with peripheral neuropathy were enrolled in a 14-week study to measure potential benefits from acupuncture, amitriptyline (Elavil, an antidepressant), the combination of acupuncture and amitriptyline, or placebo. Placebo acupuncture consisted of acupuncture needles inserted at points that were not true acupuncture points as defined by a standard acupuncture text; true insertion points were agreed upon by eight experienced acupuncturists.

The results at six and 14 weeks showed no significant differences among the four groups. Those who received true acupuncture experienced a mild decrease in pain scores at 14 weeks compared to those receiving amitriptyline or placebo, but the differences were not significant. Similarly, those receiving amitriptyline experienced a mild decrease in pain scores at six weeks when compared to the other therapy or placebo; these differences were also not significant.

The results of this study do not necessarily indicate that any individual person may not derive some benefit from the therapies. The authors note that the "non-true" needle insertion sites may have provided some benefit. Also, many acupuncturists individualize acupuncture treatments. Lastly, many healers using eastern techniques say that western placebo-controlled, double-blind studies are unable to measure the benefits of their therapies.

Acupuncture has shown efficacy for nausea and vomiting after chemotherapy, and for anesthesia recovery after surgery. It has also shown benefits in pain after dental surgery. There are many other conditions for which acupuncture has a demonstrated, adjunctive role to western therapies.

Shlay, J.C. and others. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy. Journal of the American Medical Association 280:1590-1595. November 11, 1998.

Pneumococcal Vaccine Response and Viral Load

• Response to the pneumococcal vaccine (Pneumovax) was better in people with lower HIV viral loads.
• Patients with HIV viral load less than 10,000 copies/mL had better antibody responses to the vaccine.
• No correlation between vaccine response and CD4 count was seen.

Fleming, C.A. and others. Immunogenicity of pneumococcal vaccine in HIV-infected patients: correlation with CD4 count and plasma viral load. 38th ICAAC. Abstract I-187.

Pre-HAART CD4 Count Predicts PCP

• CD4 count before the initiation of anti-HIV therapy correlates with future risk of Pneumocystis carinii pneumonia (PCP).
• Pre-HAART CD4 count also correlates with future risk of any HIV disease progression.

One of the ongoing controversies in HIV/AIDS treatment is whether prophylaxis (preventive therapy) for opportunistic infections can safely be stopped after anti-HIV therapy leads to increases in CD4 count increase (see "Opportunistic Infections: Is it Safe to Stop Prophylaxis?" this issue). Before the era of antiretroviral therapy, the risk for developing PCP increased markedly when the CD4 count dropped below 200 cells/mm³. Several reports to date have indicated that after anti-HIV therapy causes the CD4 count to increase to greater than 200 cells/mm³, the subsequent risk for PCP and several other opportunistic infections decreases markedly. If PCP does develop in people with increased CD4 cell counts, it usually occurs within the first few months after antiretroviral therapy is started.

Now, researchers from the CDC have found another risk factor for developing PCP after HAART-induced CD4 count increases. A total of 5,158 patients were included in the analysis. The CD4 count before starting anti-HIV therapy was found to correlate with future PCP incidence, even when CD4 count increased to greater than 200 cells/mm³. The lower the CD4 count before anti-HIV therapy was started, the higher the subsequent risk for PCP after starting therapy. People whose lowest (nadir) CD4 count was less than 24 cells/mm³ had an eleven-fold increased risk, while those with a CD4 nadir between 25-149 cells/mm³ had a five-fold increased risk. These two groups were compared with people whose lowest CD4 count was at least 150 cells/mm³. Only people who never had PCP previously were included.

These results will be helpful for physicians and people with HIV who are wrestling with whether to continue or discontinue PCP prophylaxis after anti-HIV therapy has increased the CD4 cell count to greater than 200 cells/mm³. Even those who have never had PCP may be wise to continue prophylaxis if their lowest CD4 count was less than 150 cells/mm³, and even more so if their lowest count was less than 25 cells/mm³.

There was a related presentation from the EuroSIDA Study Group. Fifty centers across Europe enrolled 7,230 HIV positive patients who were followed prospectively for a median of 13 months. The CD4 count before anti-HIV therapy was found to correlate with subsequent HIV disease progression, even after the count increased to greater than 200 cells/mm³. HIV progression rates for those whose lowest count was less than 50 cells/mm³ was over twice that for those whose lowest count was never less than 150 cells/mm³.

These two reports indicate that the improvement in immune response due to anti-HIV therapy is only partial, at least in the first year or so after potent antiretroviral therapy is started.

Miller, V. and others. Disease progression in patients with HIV-1 infection--relationship with antiretroviral treatment and increasing CD4 lymphocyte counts. 4th ICDTHI. Abstract OP6.1.1

Synercid for Toxoplasmosis

• Synercid (quinupristin plus dalfopristin), a streptogramin antibiotic, has efficacy against Toxoplasma gondii in vitro and in an animal model.

Kahn, A.A. and others. Synercid is active against Toxoplasma gondii. 38th ICAAC. Abstract B-62.

The CDC has updated its guidelines for the treatment of active tuberculosis (TB) disease in persons with HIV who are taking HAART (see "Tuberculosis," BETA, October 1998). The update includes three options:

Option 1 (six to nine months duration)

• Rifabutin at half dose is substituted for rifampin.
• Daily isoniazid (300 mg) plus rifabutin (150 mg) plus pyrazinamide (25 mg/kg) plus ethambutol (15 mg per kg), all for two months.
• For the next four to seven months, continue with either daily isoniazid (300 mg) plus rifabutin (150 mg), or twice weekly isoniazid plus rifabutin (300 mg).

The HAART regimen of persons using Option1 may include indinavir, nelfinavir, amprenavir, or efavirenz, but should not include ritonavir, hard-gel saquinavir (Invirase) or delavirdine; to date, there are limited data about soft-gel saquinavir (Fortovase) and nevirapine.

Dose levels of protease inhibitors or NNRTIs may have to be increased 20-25% to maintain adequate blood levels. When co-administered with rifabutin, the indinavir dose may need to be increased to 1,200 mg every 8 hours, nelfinavir dose may need to be increased to 1,000 mg every 8 hours, amprenavir dose may need to be increased (based on limited data), and dose increases of other antiretroviral drugs are uncertain due to limited data. If the HAART regimen includes efavirenz, the daily or twice weekly dose of rifabutin should be increased to 450 mg.

Monitoring for rifabutin toxicity (indicated by joint aches, eye inflammation, low blood white cell count, and hepatitis) is indicated for people taking HAART. Rifabutin is known to decrease blood levels of methadone, oral contraceptive hormones, dapsone, and ketoconazole. Regular HIV viral load testing should be done to rule out possible viral load rebound associated with low blood levels of protease inhibitors or NNRTIs.

Option 2 (nine to twelve months duration)

• Rifamycin drugs (rifampin, rifabutin, rifapentine) are excluded.
• Daily isoniazid (300 mg) plus pyrazinamide (25 mg/kg) plus ethambutol (15 mg/kg) plus streptomycin (15 mg/kg), all for two months.
• For the next seven to ten months, continue with all three antibiotic drugs two to three times weekly.

The HAART regimen for people using Option 2 may include any protease inhibitor or NNRTI.

Streptomycin should not be taken by pregnant women due to fetal toxicity. The drug may cause ear and kidney toxicity. Streptomycin is only available by intramuscular injection or intravenously.

Option 3 (six to nine months duration)

• Daily isoniazid (300 mg) plus rifampin (600 mg) plus pyrazinamide (25 mg/kg) plus ethambutol (15 mg/kg), all for two months.
• For the next four to seven months, continue with either daily or twice-weekly isoniazid plus rifampin.

Option 3 is only for people not taking anti-HIV therapy, or for those taking only nucleoside or nucleotide anaolgs (i.e., no protease inhibitors or NNRTIs).

Stopping HAART in order to start TB treatment is not recognized as an option in the revised guidelines. Directly-observed therapy (DOT) is recommended whenever possible for all patients with HIV-related tuberculosis. The revised guidelines recognize the paradoxical "immune flare" reaction that may occur when starting HAART with anti-TB therapy.

  Page last updated 15 January 1999

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