(BETA) Research Notes: Part 2

Bulletin of Experimental Treatments for AIDS, July, 1998
Harvey S. Bartnof, MD

Protease Inhibitor Side Effects

Possible Hair Loss Due to Indinavir

Researchers at the University of Milan, Italy, reported on 5 patients who developed severe hair loss that the physicians attributed to the use of indinavir. The report leaves open the possibility that other drugs were responsible. These 5 are 1.5% of the total of 337 patients at that institution who were given indinavir in various combinations with nucleoside analog drugs. All 5 were receiving triple combination anti-HIV therapy. Three took indinavir plus 3TC plus d4T, one took indinavir plus AZT, and 1 took indinavir plus ddI. Hair loss was clinically apparent an average of 50 days after initiating therapy. None showed evidence of hair re-growth within a median of 30 days after indinavir was stopped. Other follow up information was not given.

Before starting triple drug therapy, median CD4 cell count was 112 cells/mm³, while the median HIV RNA viral load was 12,500 copies/mL. At the time of hair loss diagnosis, the median viral load was undetectable (fewer than 500 copies/mL).

Some people, including HIV negative individuals, experience hair loss associated with an abnormal immune response to their own hair follicles. The medical literature reports partial or complete hair loss associated with untreated HIV infection. One published case report associated hair loss with AZT and another with 3TC. Since all 5 patients in the Italian report took either AZT or 3TC, these drugs cannot be ruled out as the cause of hair loss.

The authors stated that they were unsure if hair loss was associated with partial immune reconstitution resulting from triple anti-HIV therapy. They concluded that people taking indinavir should be monitored for hair loss and that the drug should be discontinued if it occurs. When choosing protease inhibitors, patients should be aware of this possible side effect of indinavir or other protease inhibitors, or of AZT or 3TC.

Fong IW. Hair loss associated with lamivudine. The Lancet 344:1702. December 17, 1994.

Geletko SM and others. Alopecia associated with zidovudine therapy. Pharmacotherapy 16:79-81. January 1996.

Monforte A and others. Indinavir-related alopecia. AIDS 12:328. 1998.

Smith KJ and others. Clinical and histopathologic features of hair loss in patients with HIV-1 infection. Journal of the American Academy of Dermatology 34:63068. January 1996.

Lowered Blood Pressure Due to Indinavir

Belgian researchers have reported that they believe indinavir was the cause of a severe, life-threatening allergic reaction in 1 man. The reaction included low blood pressure (down to 60/40 from a normal level of 120/80), fever, hepatitis with jaundice (yellowing of the skin), neutropenia (low white blood cell count) and rash. The authors said that the abnormalities occurred 3 separate times after starting or restarting indinavir and resolved after it was discontinued. The third challenge was done only after specific informed consent. Because of potential confounding effects from other concurrent drugs, the authors acknowledged that they "cannot exclude the possibility that an interaction between 3TC, ganciclovir (Cytovene) and indinavir is necessary to induce this severe allergic reaction to indinavir." The patient was antibody negative for hepatitis A and B; hepatitis C status was not reported. This may have been another potential confounding factor, although his liver function tests returned to normal after indinavir was discontinued.

Rijnders B and other. Severe allergic reaction after repeated exposure to indinavir. Clinical Infectious Diseases 26:523-524. February 1998.

Myasthenia Gravis Due to Ritonavir

Neurologists from the University Hospitals of Cleveland have reported the occurrence of ritonavir-induced myasthenia gravis in 1 patient. Myasthenia gravis is an autoimmune disease of nerve-muscle junctions that causes muscle weakness. It is usually a progressive disease that is treatable. The 71-year-old HIV positive man added ritonavir to his HIV treatment regimen of AZT plus 3TC 3 weeks prior to the onset of symptoms, which included slurred speech, difficulty climbing stairs and obvious symmetrical weakness of facial muscles. Current treatment guidelines recommend against adding a single HIV medication to a regimen. His CD4 cell count was 290 cells/mm³ and his HIV viral load was not stated. The diagnosis was confirmed, in part, after muscle improvement with intravenous edrophonium. HIV therapy was stopped and the man had a good response to oral mestinon, a standard treatment for myasthenia gravis. Later, ddI and 3TC were started. When mestinon was later discontinued, however, symptoms of myasthenia gravis recurred. The man had a prior history of rheumatoid arthritis, another autoimmune disease. While this is the first report of myasthenia gravis associated with ritonavir, the authors believe that the frequent complaint of fatigue by HIV patients treated with ritonavir "may in some way be related to development of myasthenia gravis." Fatigue, however, is a common symptom with HIV infection and can also occur as a side effect of many drugs.

Saadat K and others. Ritonavir-associated myasthenia gravis. Muscle and Nerve 680-681. May 1998.

Intravenous L-Carnitine Increases CD4 Cell Counts

In a pilot study, researchers from the University La Sapienza in Rome, Italy, have reported that intravenous L-carnitine was beneficial for HIV positive people. Carnitine occurs naturally in humans, and inhibits apoptosis, or programmed cell death. Apoptosis is believed to play a role in the progressive decline in CD4 cell counts during the course of HIV disease. Carnitine is thought to down-regulate abnormally high levels of ceramide in lymphocytes that occur in untreated people with AIDS, but are absent in long-term HIV non-progressors.

Eleven HIV positive drug-injecting men in an addiction-recovery program volunteered for the trial. All were asymptomatic with progressively declining CD4 cell counts (median 331 cells/mm³); all had 200-500 cells/mm³. Baseline median HIV

viral load was 3.8 log copies/mL. All 11 men refused standard anti-HIV therapy but consented to the experimental L-carnitine therapy. All 11 had total baseline carnitine levels equivalent to those in HIV negative persons. Treatment consisted of daily, 2-hour infusions of 6 grams of L-carnitine for 4 months.

The median CD4 cell count increased progressively and significantly from 331 to 476 cells/mm³. The CD8 cell count increased insignificantly from 844 to 947 cells/mm³. HIV RNA viral load increased slightly but not significantly from 3.84 log to 4.04 log copies/mL. Researchers also measured a significant decrease in the frequency of apoptotic CD4 and CD8 cells. Also, a significant reduction of ceramide in lymphocytes was measured. The therapy was well tolerated without apparent side effects. All 11 participants finished therapy without dose reduction. All 11 also reported a "sense of well-being" by the second week of carnitine infusions.

The authors hypothesized a possible dissociation between HIV viremia and CD4 cell depletion. Randomized studies continue to compare combination antiretroviral therapy with and without L-carnitine supplementation. For those patients whose HIV has become resistant to standard drug regimens, L-carnitine may play a role in salvage therapy.

Moretti S and others. Effect of L-carnitine in human immunodeficiency virus-1 infection-associated apoptosis: a pilot study. Blood 91(10):3817-3824. May 15, 1998.

Opportunistic Conditions

International AIDS Society Publishes New Consensus Treatment Guidelines for CMV

The International AIDS Society (IAS-USA) assembled a 17-member panel of prominent physician-researchers to develop consensus treatment guidelines for cytomegalovirus (CMV) disease. The panel deliberated in 1997 and submitted a paper for publication in January 1998. It appeared in the May 11, 1998 issue of Archives of Internal Medicine. Data from the Fifth Conference on Retroviruses and Opportunistic Infections was not included (see BETA, April 1998).

BETA has published information about current state-of-the-art treatments for CMV (see Fomivirsen, BETA, April 1998, and Cidofvir, this issue).

Treatments for CMV include 1 or more of the following:

1. intravenous (IV) ganciclovir (Cytovene), also available as a capsule, implant or intraocular injection
2. intravenous foscarnet (Foscavir), also available as an intraocular injection
3. intravenous cidofovir (Vistide)

The benefits and side effects of each are well characterized.

Specific recommendations include the following general principles:

• Patients with HIV infection should be educated about the symptoms of CMV retinitis (eye inflammation) and advised to seek care in a timely manner after the onset of visual symptoms. The importance of regular eye examinations and medical follow-up should be stressed.
• Many experts recommend that patients at high risk for CMV disease should have ophthalmologic screening (eye exams, including indirect ophthalmoscopy) every 3-6 months. Before the availability of HAART, patients at risk for CMV disease included those who were positive for antibodies against CMV and who had CD4 cell counts less than 50 cells/mm³. Some experts screen patients with CD4 cell counts less than 100 cells/mm³. Patients with any previous diagnosis of CMV disease should also be examined regularly.
• A diagnosis of CMV retinitis should trigger a thorough examination for CMV outside of the eye and vice versa. Regular ophthalmic and medical examinations should continue for life.
• Successful management of CMV retinitis requires close collaboration between the ophthalmologist and the treating physician.

Eye examination recommendations:

• Ophthalmologic examinations should be performed immediately before treatment is begun, after treatment is completed (first episode and subsequent relapses) and monthly thereafter.
• Examination schedules should be individualized for patients on the basis of ophthalmologic factors and response to treatment.
• Patients should return immediately for follow-up examinations if new eye symptoms develop.
• Use of retinal photographs in conjunction with regular clinical examinations is the optimal means of monitoring patient status.

Treatment recommendations for CMV retinitis:

• Treatment should be individualized based on unique characteristics of ophthalmologic disease, underlying medical condition, living conditions and lifestyle preferences.
• Daily infusions of ganciclovir or foscarnet, or weekly then biweekly IV infusions of cidofovir, are each appropriate initial choices for induction and maintenance therapy for CMV retinitis.
• The ganciclovir implant is an appropriate choice for initial therapy for CMV retintis.
• Many experts consider the implant to be the preferred choice for patients with immediately sight-threatening disease.
• Oral ganciclovir should not be used as the sole form of induction therapy for any patient and should not be the sole form of maintenance therapy for patients with immediatedly sight-threatening disease.
• Oral ganciclovir may be an appropriate choice for maintenance therapy for patients whose retinitis does not immediately threaten their vision.
• In certain circumstances, intermittent intravitreous (into the eye) injections of ganciclovir or foscarnet may be an appropriate choice for induction and maintenance therapy. Concomitant systemic anti-CMV therapy (e.g., oral ganciclovir) is recommended with any local intraocular therapy.

Relapsing and refractory CMV retinitis recommendations:

• The treatment of relapsing retinitis and refractory disease should be individualized and depends on several factors, including other health measures (e.g., kidney function), previous therapy and retinitis disease history.
• For simple relapsing retinitis, re-induction with any available induction treatment (including the same drug that the patient initially received) is acceptable.
• For refractory disease, re-induction with combination therapy including a different induction drug or with local therapy is recommended.

CMV gastrointestinal disease recommendations:

• Induction therapy with IV ganciclovir or IV foscarnet for symptomatic CMV gastrointestinal disease should be given for 3-6 weeks depending on clinical circumstances.
• Maintenance therapy should be considered, particularly after re-induction for a relapse. The role of oral ganciclovir has not yet been established, but may be a reasonable option.
• Combination IV ganciclovir and IV foscarnet therapy may be effective after monotherapy has failed.
• Patients with CMV gastrointestinal disease should undergo regular ophthalmologic screening for CMV retinitis.

CMV neurologic disease recommendations:

• A high index of suspicion for CMV neurologic disease must be maintained and therapy should be initiated as soon as possible.
• Therapy with IV ganciclovir or IV foscarnet or a combination of the 2 drugs is recommended; combination therapy should be considered for patients who have received prior anti-CMV therapy.
• Patients with neurologic CMV disease should undergo regular ophthalmologic screening for retinitis.

CMV lung disease recommendations:

• CMV should be considered the cause of pneumonitis (lung inflammation) in an HIV-infected person who meets specific diagnostic criteria; treatment is recommended.
• Therapy for CMV pneumonitis should be considered in a patient with co-infection with another pulmonary pathogen who does not respond to therapy directed against the other pathogen.
• Therapy with IV ganciclovir or IV foscarnet for at least 21 days is recommended for patients with CMV pneumonitis.
• Long-term suppressive therapy after treatment for CMV pneumonitis is not recommended unless there is a documented relapse or evidence of disease outside the lung.

Other CMV diseases recommendations:

• CMV viremia (virus in the blood) may be associated with subclinical (asymptomatic) involvement of other organ systems (e.g., adrenal glands, liver, gall bladder/bile tract, pancreas). In the symptomatic patient with CMV viremia without other treatable pathogens identified after a thorough evaluation, a therapeutic trial of ganciclovir or foscarnet may be warranted.

Recommendations for CMV retinitis in patients who respond to HAART:

• All HIV-infected patients with CMV disease should receive potent combination antiretroviral therapy as tolerated and according to recommended guidelines.
• Generally, patients in whom CMV has been diagnosed should be advised to continue their anti-CMV maintenance therapy because the effect of potent antiretroviral therapy on the course of CMV disease is still poorly understood.

The recommendations regarding CMV retinitis treatment in the context of a response to HAART is conservative but reasonable. The incidence of CMV disease has sharply decreased due to HAART. Presentations at the 5th Conference on Retroviruses and Opportunistic Infections support this position. In 1994 and 1995, there were 48 and 46 cases, respectively, of CMV disease diagnosed at San Francisco General Hospital. In the first half of 1997, there was only 1. People who respond to HAART (with significant CD4 cell count increases and undetectable or low HIV RNA viral load) for 12 months or longer, are adherent to their treatment regimen and have a negative CMV antigen or PCR test result may be candidates for discontinuing their anti-CMV prophylaxis under the guidance of their physicians. Do not stop taking any medication without first consulting a physician. However, at the slightest hint of faltering efficacy of HAART or any visual problems, it may be necessary to re-start CMV prophylaxis. The IAS-USA guidelines will probably be modified to reflect epidemiological documentation when the panel again convenes.

Physician panel members included Richard Whitley, MD, Mark Jacobsen, MD, Dorothy Friedberg, MD, Gary Holland, MD, Douglas Jabs, MD, Douglas Dieterich, MD, David Hardy, MD, Michael Polis, MD, Thomas Deutsch, MD, Judith Feinberg, MD, Stephen Spector, MD, Sharon Walmsley, MD, Lawrence Drew, MD, William Powderly, MD, Paul Griffiths, MD, Constance Benson, MD and Harold Kessler, MD.

Holtzer CD and other. Decline in specific opportunistic infections at San Francisco General Hospital. 5th Conference on Retroviruses and Opportunistic Infections. Chicago. February 1998. Abstract 183.

Moore RD and others. Decline in CMV and other opportunistic disease with combination antiretroviral therapy. 5th Conference on Retroviruses and Opportunistic Infections, Chicago. February 1998. Abstract 184.

Walsh JC and others. Increasing survival in AIDS patients with cytomegalovirus retinitis treated with combination antiretroviral therapy including HIV protease inhibitors. AIDS 12:613-618. 1998.

Whitley RJ and others. Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy – recommendations of an international panel. Archives of Internal Medicine 158:957-969. May 11, 1998.

Should Testosterone Be Given to HIV Positive Men with Normal Blood Levels?

HIV positive men commonly have low blood levels of sex hormones, which may lead to wasting and symptoms of altered libido, mood, energy and appetite. Wasting may continue even with therapeutic viral load and CD4 cell responses to HAART. Low testosterone levels are treated with supplemental hormone injections. Some HIV physicians offer testosterone supplementation if the blood level of testosterone is in the lowest third of the normal range (less than approximately 500 nanograms per deciliter).

A provocative exploratory study has examined the use of testosterone injections in HIV positive men with symptoms of low testosterone, but who have normal blood levels of the hormone -- i.e., those in the middle third of the normal range. The study enrolled 23 men (44% were racial/ethnic minorities) for a 12-week open-label trial of biweekly intramuscular injections of testosterone cypionate. The first injection was 200 mg and all subsequent ones were 400 mg. The dosage was decreased or injections were withheld if adverse reactions occurred or if blood testosterone levels exceeded twice the upper limit of the normal range. All men had reported decreased libido and at least 1 of the following symptoms: low mood, low energy, or loss of appetite and/or weight loss. Symptoms were scored on the Clinical Global Impressions Scale.

The mean baseline CD4 cell count was 150 cells/mm³; HIV RNA viral load level was not stated. All patients had an AIDS diagnosis. The baseline range of blood serum testosterone was 502-671 nanograms per deciliter. At baseline, 65% of enrollees were taking anti-HIV therapy (specifics were not stated).

Nineteen of 23 (83%) completed the study. Four dropped out of the study because of new AIDS-related illness, alcohol abuse or loss to follow-up. The results indicated a significant improvement in mood, energy and libido, but not appetite, which showed a non-significant increase. Body weight and body cell mass also increased significantly. Fat mass remained the same. No side effects were reported by 48% of the men. The remaining men reported 1 side effect each, usually either irritability or acne. Effects on CD4 cell counts and HIV viral load were not stated.

The authors acknowledged that since people with HIV/AIDS are living longer due to HAART, the long-term side effects of testosterone therapy may outweigh potential benefit. They stated that a randomized, controlled trial is needed.

Limitations of the study included the participation of individuals with untreated major depressive illness. The authors acknowledged that 7 of 23 participants (30%) were diagnosed with major depression at baseline. There was no mention of their having been treated for that psychiatric diagnosis. The study authors have PhD (not MD) degrees from the Department of Psychiatry at the New York State Psychiatric Institute. In addition, participants' thyroid status was not mentioned. Low thyroid hormone levels could cause several or all of the symptoms under study.

Wagner GJ and other. Testosterone therapy for clinical symptoms of hypogonadism in eugonadal men with AIDS. International Journal of STD and AIDS 9:41-44. January 1998.

KSHV/HHV-8 and HIV Co-Infection Leads to Kaposi's Sarcoma in 50% after 10 Years

• 38% of gay/bisexual men are positive for antibodies to human herpesvirus type 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV).
• Risk of HHV-8 antibody positivity increases with increasing numbers of male sex partners during the previous 2 years
• The San Francisco Men's Health Study included 800 men

Martin JN and others. Sexual transmission and the natural history of human herpesvirus 8 infection. The New England Journal of Medicine 338:948-954. April 2, 1998.

HHV-8 is Readily Detected in Saliva and Nasal Secretions

Tuberculosis Strains Usually Do Not Cross the San Francisco Bay

Mycobacterium tuberculosis is the only opportunistic organism in people with AIDS that is transmitted by the airborne route. Given the emergence of multidrug-resistant tuberculosis (TB) strains and the 370,000 persons crossing the San Francisco Bay Bridge daily, the potential spread of TB has significant public health implications. Researchers from the University of California at San Francisco compared the genetic patterns of tuberculosis strains in San Francisco with those of the East Bay (Alameda and Contra Costa counties).

Among 724 TB isolates from new TB patients between 1992-1993, only 53 (7%) genetically matched 1 or more isolates from the other region. Of 375 unique TB isolates from San Francisco, only 9 (2%) had a matching pattern with an East Bay isolate. A matching isolate from both sides of the bay was statistically more common among people with AIDS and among those with a non-Asian ethnic background. The results indicate that TB does not usually cross the geographic boundary of the San Francisco Bay and that public health preventive campaigns could retain a local focus.

Bradford WZ and others. Dissemination of Mycobacterium tuberculosis across the San Francisco Bay Area. The Journal of Infectious Diseases 177:1104-1107. April 1998.

Sensory Neuropathy Successfully Treated with Gabapentin

Painful sensory neuropathy in the feet and sometimes in the fingers affects 30-59% of persons with HIV. It is detected in virtually 100% of people with AIDS upon autopsy examination. Symptoms include burning pain, a "pins-and-needles" sensation, numbness and cramping. The cause is believed to be HIV, possibly CMV, and related vascular inflammation. Certain medications used to treat HIV/AIDS and associated opportunistic conditions also can cause neuropathy, including d4T, ddI, ddC, isoniazid (used to treat TB), foscarnet (used to treat CMV) and vincristine (a cancer chemotherapy). Treatment is difficult and includes anti-depressants, opiates, topical capsaicin and acupuncture.

G. Newshan, MD, from St. Vincent's Hospital in New York City, reported a 100% success rate in treating 3 different patients who had sensory neuropathy with gabapentin. This drug is FDA approved as an anticonvulsant (anti-seizure) therapy. None of the 3 patients had responded to standard therapies. Two started on a 300 mg dosage of gabapentin at bedtime, while the third started at 300 mg 3 times daily. All had their doses gradually increased after partial improvement. The final dosages were 300 mg 3 times daily, 600 mg 3 times daily and 600 mg every 12 hours.

Gabapentin is excreted by the kidneys, and drug interactions with the protease inhibitor drugs in the liver are not a problem; indinavir is secreted by the kidneys, however none of the 3 patients were taking indinavir. Antacids decrease the bioavailability of gabapentin by 20% if given within 2 hours of an oral dose. Common side effects are sleepiness (19%), dizziness (17%), balance problems (12%) and weakness (11%). Capsules are available in 100, 300 or 400 mg doses. The effective daily dose range is 900-1,800 mg in divided doses (usually 3 times daily). Those with painful sensory neuropathy that has been difficult to treat may want to ask their physician about a trial of gabapentin (with a caution for those taking indinavir).

Newshan G. HIV neuropathy treated with gabapentin. AIDS 12(2):219-221. February 1998.

Once-Daily Sorivudine is as Effective as 5-Times-Daily Acyclovir for Shingles

The painful blister rash of shingles occurs 15 times more frequently among HIV positive than among HIV negative persons. Shingles is a reactivation of varicella-zoster virus (VZV), a herpesvirus that causes chickenpox in childhood. Sorivudine is a new antiviral drug with more activity, better absorption and a longer half-life in blood than the standard therapy for shingles, acyclovir (Zovirax).

Researchers from the Collaborative Antiviral Study Group and the Herpes Zoster Study Group of the AIDS Clinical Trials Group (ACTG) have published a study of this new therapy for shingles. The randomized, double-blind, placebo-controlled, multicenter trial enrolled 170 HIV positive participants (10% women) with acute shingles rash. Participants received a 10-day course of either 40 mg daily of sorivudine plus acyclovir placebo, or acyclovir 800 mg 5 times daily plus sorivudine placebo. Participants were assessed for up to 1 year.

Sorivudine was 48% more effective than acyclovir in reducing the time to cessation of new blister formation. In addition, it was significantly more effective (54%) than acyclovir in reducing the time until total lesion crusting. There was no difference between the 2 therapies in time to resolution of shingles pain, spreading of VZV to new skin locations or rate of shingles recurrence up to 1 year.

An attractive feature of sorivudine is once-daily dosing. However, the daily cost of sorivudine will be more than that of acyclovir 800 mg 5 times daily. In an era of managed care, budgets usually force healthcare poviders to choose the least expensive therapy for a given diagnosis.

The authors indicated that FDA is unlikely to approve sorivudine for use in the U.S. because 18 deaths occurred among HIV negative Japanese cancer patients who were given sorivudine in 1993. They were also given the cancer chemotherapy drug 5-fluorouracil. Sorivudine indirectly inhibits metabolism of 5-FU, leading to excess bone marrow toxicity. Sorivudine was withdrawn from the Japanese market only 1 month after its approval. It is uncommon to use 5-FU in the treatment of people with HIV/AIDS. No patient in the current trial was allowed to take it with sorivudine. After the trial was concluded, Bristol-Myers Squibb discontinued development of sorivudine because of concerns that FDA may have about the Japanese fiasco.

Gnann JW and others. Sorivudine versus acyclovir for treatment of dermatomal herpes zoster in human immunodeficiency virus-infected patients: results from a randomized, controlled clinical trial. Antimicrobial Agents and Chemotherapy 42:1139-1145. May 1998.