Important note: Information in this article was accurate in May 2001. The state of the art may have changed since the publication date.
Editor's Note: The Johns Hopkins AIDS Website (http://hopkins-aids.edu) features the Clinician Forum, an interactive question and answer resource exclusively for health care providers. Physicians, nurses and other clinicians caring for patients may submit questions about clinical problems and dilemmas, receiving prompt answers from more than 15 Johns Hopkins faculty involved in HIV clinical care and research. The exchange of information on the Clinician Forum serves as a barometer for the rapidly evolving field of HIV therapy, and many complex problems are dealt with here before there are any publications available in the literature. Below is a recent sampling of some of the postings from the Forum. We encourage readers of the HHR to visit the site to see more, and to submit their own queries regarding patient management.
Elevated Liver Enzymes Due to Steatohepatitis
Answered by Richard D. Moore, M.D., 3/30/01
Q: I have several patients who have had mildly elevated transaminases (2-3 times normal) for several years. Initial evaluations, usually prior to antiretroviral therapy (ART), revealed steatohepatitis. On ART, the liver enzymes remain slightly elevated without significant change. The remainder of the chemistry tests are normal and if the patients had abnormal lipid panels, they were treated. Given the concern about more severe liver toxicities that include fatty infiltration, how would you manage these persons?
A: You did not say how they were diagnosed with steatohepatitis, or what other risk factors may have been present. One of the more common reasons for a pre-existing fatty liver is alcohol abuse. Other possible causes include obesity, diabetes, hyperlipidemia, total parenteral nutrition, and the use of certain drugs. Have you checked the venous or arterial serum lactate level? An elevation to 5 mmol or higher would be a cause for concern and for considering discontinuing or changing NRTIs. A low serum bicarbonate and an elevated anion gap can occur if an acidosis develops from the lactic acidemia. You did not say how the steatohepatitis was diagnosed, but a CT scan alone may not be entirely accurate in making the diagnosis, and chronically elevated transaminases can be due to other factors such as hepatitis.
The nucleoside analogs are associated with the development of an hepatic steatosis-lactic acidosis syndrome, thought to be due to mitochondrial toxicity. Clinical studies suggest that d4T may be associated with the greatest risk, but all the NRTIs can potentially cause this syndrome. The protease inhibitors can also be associated with liver enzyme abnormalities, but not usually with steatohepatitis. Of the NNRTIs, nevirapine and delavirdine are more likely to cause liver enzyme elevations (and even liver failure) than is efavirenz. For a patient with biopsy-proven steatosis, you could avoid the use of an NRTI by using a dual PI + NNRTI regimen.
However, as noted above, such a regimen does not necessarily avoid liver toxicity, and liver enzymes need to be monitored. An NRTI can be used if the steatosis is mild and there is no evidence of lactic acidemia. Based on in vitro studies of mitochondrial toxicity, abacavir and 3TC may have the lowest risk for lactic acidosis-hepatic steatosis. Don't forget to identify and, if possible, remove other risk factors such as alcohol use.
Intensify or Change?
Answered by Joel E. Gallant, M.D., M.P.H., 3/22/01
Q: My patient is a 35 year old HIV/HCV co-infected man. Unfortunately, a complete past medical history is not available, although we know he was on AZT/3TC for at least 1 year, and he doesn't remember ever being on an NNRTI. His current regimen is d4T, 3TC, amprenavir, all at standard doses. He was on this regimen when he was incarcerated one year ago. AST/ALT have fluctuated between high normal and 2x upper limit of normal:
3/00: CD4 525 cells/mm3, VL <50 c/mLIs it worth trying to intensify with 100 mg bid RTV and reducing APV to 600 mg bid and/or adding ABC? Or should I go ahead and change to something like d4T/ddI/EFV with or without Kaletra? I'm a little bit worried about adding RTV either alone or in the form of Kaletra, due to his hepatitis C.
A: This patient has two important TAMs (thymidine analog mutations) and several secondary PI mutations commonly seen in patients on APV. However, he should still have a pretty good response to other PIs, and he appears to be naive to NNRTIs. Continued therapy with this regimen would be likely to increase his PI resistance and nucleoside analog resistance, however.
His next regimen will probably need to combine PIs with NNRTIs, since NRTIs are now somewhat unreliable. You may still get some activity out of abacavir, ddI, or even AZT (with 3TC), however, provided they are part of a more suppressive regimen.
You could certainly try intensifying APV with RTV, perhaps adding abacavir at the same time. There would probably be little harm in that strategy, provided you switched to a more suppressive regimen quickly if it didn't work.
It would be interesting to know what this patient's baseline viral load and CD4 count were. I ask that because we don't know for certain how badly he needs to be on therapy, nor do we know whether his viral load is still being suppressed or is close to baseline. In people with healthy CD4 counts for whom I don't have that information, I sometimes stop therapy altogether in order to establish a baseline and to be sure they really need to be on treatment.
Chronic, Non-Suppressive Therapy
Answered by Joel E. Gallant, M.D., M.P.H., 3/21/01
Q: I have a 33 year old male in my practice who came to me on Combivir alone with a viral load of around 3000 c/mL. He has been on ART for 41/2 years, starting on AZT, with 3TC added 4 or 5 months later, followed by the addition of nevirapine. His initial CD4 count was around 500 cells/mm3, with a viral load around 12,000 c/mL. His CD4 went up to around 1100 cells/mm3 and is now around 750 cells/mm3 with a similar CD4 percentage (33%). A genotype shows M184V, K70R, and K103 mutations. At my suggestion, he is no longer taking nevirapine, with maintenance of his CD4 and VL. I question the utility of continuing non-suppressive therapy; his CD4 seems to have responded and that response appears to have been maintained. The viral load is almost a log lower; the M184V mutation may be sensitizing his virus to AZT (even with the primary 70 mutation). Up until now, he has expressed a desire to continue therapy as is. But I worry about the possible accumulation of reverse transcriptase mutations that might make completely suppressive therapy (if there is such a thing) increasingly difficult to achieve in the future, should he need that. What would you recommend and why?
A: I share your concerns. He has already developed pan-NNRTI resistance as a result of taking non-suppressive therapy. If he continues, he will also have wiped out the nucleoside class, leaving him with very poor options for future therapy. Since by today's standards he probably never needed to be on therapy in the first place, stopping therapy altogether would be a very reasonable option. If he hasn't had a genotype in awhile, I'd probably repeat one before stopping to see whether he had accumulated any additional nucleoside mutations.
Therapy Before Viral Load/CD4 Counts are Known?
Answered by Joel E. Gallant, M.D., M.P.H., 3/22/00
Q: I am an internal medicine resident and have several patients with HIV/AIDS. Recently I was asked to see a 42 year old woman who was suspected to have HIV because she had thrush and her husband recently died from AIDS. She previously had been checked and was found to be negative for HIV. After seeing her, I received a report that she is HIV-infected. She appears quite cachectic, has thrush and severe depression. I have yet to receive her viral loads/CD4 counts. Would it be wise to start her on HAART assuming she probably has high counts? My choice would be to use Combivir with Sustiva or Kaletra. Any wisdom you can share would be greatly appreciated.
A: Antiretroviral therapy is rarely an emergency. At Hopkins, it takes about 48 hours to get a CD4 count and viral load back. Even if you're using a send-out commercial lab, you should have the information back within a week. This woman's condition is chronic, and it has taken her a long time to get where she is today. A few more days are unlikely to make any difference. Furthermore, her severe depression may be a more immediate problem than her HIV infection. Giving antiretroviral therapy to someone who is severely depressed is a recipe for resistance and drug failure, because depression has been shown to be associated with non-adherence. I would suggest that you get her started on treatment for her depression and her thrush while you wait for her lab results to come back. Use this opportunity to educate her about HIV disease and its treatment, and start her on therapy after her depression has begun to improve.
HIV-2 vs. HIV-1
Answered by Thomas C. Quinn, M.D., 1/1/01
Q: I have 2 patients from Zambia. The female patient was diagnosed with HIV here in the U.S., and her initial CD4 count was 2 cells/mm3. She tested negative for HIV-2. She is doing well on ddI/d4T/NFV. Her boyfriend was then tested, and he is positive for HIV-1 and HIV-2, and he presented with an equally low CD4 count at the onset. Do we need to retest the woman for HIV-2? Will NNRTIs work on the man because HIV-1 is present?
A: Dual infections do occur but are often hard to diagnose since antibodies to one virus overlap with the other virus. The best way of establishing dual infection is by PCR which is specific for HIV-1 and with a PCR specific for HIV-2. Peptide testing is also useful in discriminating the two infections. Treatment should be focused primarily on HIV-1 and response monitored by CD4 counts and viral load assays (which are specific for HIV-1 and not HIV-2). NNRTIs will be effective against HIV-1, but we have no data on their effectiveness on HIV-2. Because HIV-2 is less pathogenic, I would recommend treating the HIV-1 infection. If there is no response, try to find out more about the viral load of HIV-2. (Roche has an experimental assay for HIV-2 and Roche or the CDC may be able to analyze the blood for HIV-2 if necessary.)
HIV Pregnant Patient with Undetectable Virus On No Antiretroviral Medications
Answered by Jean R. Anderson, M.D., 12/24/00
Q: I have had several pregnant patients recently who are HIV antibody and HIV qualitative PCR positive but have undetectable virus on quantitative assay (bDNA) on no medications. What therapy would you suggest?
A: I would first suggest retesting to confirm HIV infection, especially if HIV antibody and qualitative PCR were performed on the same sample, and to reevaluate plasma viremia. CD4 cell count is also important to measure. Assuming that these patients are truly HIV-infected and have undetectable virus (and presumably high CD4 counts), I would still recommend therapy with AZT during pregnancy for prophylaxis against perinatal transmission, using the PACTG 076 regimen. Although vertical transmission appears to be unlikely with undetectable viremia, it has been reported. Furthermore, reduction of viral load accounted for only 17% of the effectiveness of AZT in the PACTG 076 study, suggesting an additional mode of action through pre- or post-exposure prophylaxis of the fetus. Both CD4 count and viral load should be monitored at intervals during pregnancy according to adult guidelines. If the results of these tests in follow-up would generally prompt consideration of treatment in non-pregnant adults, more appropriate combination antiretroviral therapy (i.e., HAART) should be considered and discussed with the patient. The use of scheduled Cesarean section in this scenario (assuming continued viral loads below <1000 c/mL) probably adds little if any additional benefit.
Suboptimal Therapy
Answered by Joel E. Gallant, M.D., M.P.H., 9/23/00
Q: I currently have about 80 HIV-infected people in my practice. I feel lucky to have a number of patients who are actively involved in their medical care and, in fact, that aspect of caring for HIV-infected people appeals to me. I am at relative peace with patients who decline ART, and continue to provide disease-appropriate care to them. However, I continue to struggle (in my own mind) with patients who only want to be on 1 or 2 HIV drugs despite being well counseled about the inevitable outcome of suboptimal therapy. I hate to alienate patients, but how can one in good conscience participate in that? I'm interested in your opinion. By the way, thank you for doing this forum. It's often quite helpful.
A: It would be unethical to give someone substandard antiretroviral therapy just because that's what he or she wants. You wouldn't perform unnecessary surgery on someone who asked for it, and I would like to think that doctors wouldn't treat viral infections with antibiotics to satisfy patients (though it happens all the time.) I have never had a patient insist on a one or two-drug regimen, and find it odd that this is happening to you on a regular basis. A patient who asks for inappropriate therapy needs education, not treatment. Likewise, patients who refuse antiretroviral therapy despite clear-cut indications need to be educated about the risks they're taking. You can't treat patients against their will, but you also shouldn't condone the decisions they're making by refusing to challenge them on it.
Continuing 3TC After Resistance
Answered by Joel E. Gallant, M.D., M.P.H., 12/25/00
Q: What is your current opinion regarding the continuation of 3TC in face of the 184 mutation. Some recent data suggests it will maintain a "less fit" virus (not the older data suggesting the effect on AZT sensitivity). Would you keep it on as 4th drug in some clinical situations?
A: It's always better to be sensitive to a drug than to be resistant to it, so if you had a choice you'd rather not have M184V than have it. But there are some benefits associated with this mutation: (1) M184V can reverse or prevent the emergence of the 215 reverse transcriptase mutation, which is associated with resistance to AZT and other nucleoside analogs. (2) It increases the activity of tenofovir. (3) M184V decreases replicative capacity or "fitness." This is true with other mutations, as well, but it seems to be particularly true with M184V. In a patient who has 3TC resistance but good options for suppressive therapy, I would not usually continue 3TC unless it was to prevent AZT resistance or to treat chronic hepatitis B infection. However, in someone for whom an undetectable viral load is not a realistic goal, I often continue a regimen that includes 3TC in order to decrease viral fitness and thereby delay immunologic decline and clinical progression.
Kaposi's Sarcoma and Topical Treatment
Answered by Ciro R. Martins, M.D. 3/14/00
Q: I recall that there is a topical retinol treatment for Kaposi's Sarcoma but do not remember its name. Can you help?
A: There is a retinoic acid derivative called Panretin (alitretinoin) gel. The concentration is 0.1%, and the medication must be applied as a thick layer over the lesions only, 2-3 times a day. After applying, the patients must let it air dry completely to avoid smearing to adjacent areas. It is a good idea to protect the normal surrounding skin with petroleum jelly before applying the medication. Even so, it may cause skin irritation, but it usually is not severe enough to require discontinuation of treatment. Efficacy is approximately 30% after 2 months, but it is still one of the only non-invasive therapies available. One major drawback is its high cost: approximately $2,000.00 for a 60g tube! It is FDA-approved, so many insurance companies will cover it, since there are no alternative topical medications. State AIDS pharmacy programs vary in their policies regarding coverage of this medication. If the patient is not insured, then this is definitely not a good option.
Antiretroviral Therapy in Hepatitis C Virus-Related Cirrhosis
Answered by Joel E. Gallant, M.D., M.P.H., 12/4/00
Q: A 38-year-old man with HIV/HCV coinfection has biopsy-proven cirrhosis and has been assessed at a liver transplant center. In September 2000 he developed a bilirubin of 10, ascites and increased transaminases. All antiretroviral therapy was discontinued and bilirubin has decreased to 3.8, transaminases have fallen and ascites has disappeared. He is now on diuretics. Since his ART was discontinued, his VL has rebounded from undetectable to 134,000. His CD4 count has fallen from 653 to 486. He remains asymptomatic. The patient is very keen to restart antiretroviral therapy, but with what? His antiretroviral history includes: AZT monotherapy 1993-1996; AZT+3TC 1996-1999; d4T, ddI and efavirenz 1999 (efavirenz was stopped due to CNS side effects); d4T, ddI and nelfinavir since 1999 (this was the therapy that was stopped due to the decompensation of his liver disease).
A: I would not usually start antiretroviral therapy in anyone with a CD4 count of 486, and would not even think about it in someone with cirrhosis. He is in little danger of developing HIV-related complications anytime soon, whereas his prognosis with respect to his cirrhosis is poor unless he is transplanted. Since antiretroviral therapy could cause further hepatotoxicity, it seems reasonable to defer starting it until there are stronger indications for treatment.
Impotence
Answered by Joel E. Gallant, M.D., M.P.H., 8/7/00
Q: I have many patients who are complaining about impotence, especially after HAART. Some of them are very young. I know there are many psychologic problems involved, but these drugs can affect testosterone levels too. What are you doing in these cases. Some patients are taking sildenafil. Is hormone replacement possible to use. What about the interactions with PIs and NNTRIs?
A: Hypogonadism is common among patients on therapy for HIV infection. In addition to causing impotence, it can lead to fatigue, depression, anemia, and an overall decrease in quality of life. Therefore, it's important to diagnose hypogonadism in patients experiencing any of these symptoms. Diagnosis is fairly straightforward. Morning blood should be sent for a testosterone level. A total level can be sent, but if it is normal, you may then need to go on and order a free level. Many just order both. If testosterone levels are low or in the low end of the normal range, then replacement is indicated, especially in a symptomatic man. Replacement can be achieved with injectable testosterone (e.g. testosterone enanthate 200 mg every 2 weeks) or with topical testosterone (patches such as Testoderm TTS or Androderm, or the new AndroGel formulation). There are no important drug interactions to worry about when combining testosterone with HIV therapy. Patients who complain of impotence despite normal testosterone levels can certainly take Viagra. But it's also important to rule out other possible causes, especially depression. When using Viagra with protease inhibitors (especially ritonavir-containing combinations), I start with a low dose (25 mg) and tell patients not to take Viagra two days in a row. PIs can increase Viagra levels.
Deterioration After Stopping Tuberculosis Treatment
Answered by Richard E. Chaisson, M.D., 1/30/01
Q: I would like to present to you a case that is troubling us at the moment. A 60-year-old male was first diagnosed with HIV infection at the end of 1999 along with cerebral toxoplasmosis and tuberculosis (TB). He was started on rifabutin, isoniazid, pyrazinamide, streptomycin, pyrimethamine and sulfamethoxazole. HIV treatment was added using AZT, 3TC, and ABC. The patient improved and viral load became undetectable, although CD4 count remained <100. After 1 year TB treatment was stopped. Two weeks later the patient presented in a deteriorated condition with acidosis (some lactate, but normal anion gap) progressive liver failure and disseminated intravascular coagulation. All therapies were stopped and riboflavin was given without effect. Tests for current TB and viral hepatitis were negative. The patient is now in renal failure and will start hemodialysis tomorrow. Do you have any good idea what caused the problem? What therapeutic approach would you suggest ?
A: The condition of your patient now sounds more like lactic acidosis related to HIV therapy than tuberculosis. We have seen a number of patients with lactic acidosis related to nucleoside analogs who do not have a large anion gap. Treatment of this disorder is supportive, as there are no compelling data to show that riboflavin or B complex vitamins help. Nonetheless, these are usually given anyway. I think it is unlikely that TB is related to this presentation. I would focus on supportive measures for now and avoid nucleosides in the future, unless an alternative diagnosis is made.
Travel for HIV-infected Physician
Answered by Robert C. Bollinger, Jr., M.D., M.P.H., 7/25/00
Q: I am an HIV-positive physician currently working in the U.S. My viral loads are undetectable and CD4s are in the 350s. I have not traveled to third world countries, despite having family in India, because of lack of adequate medical facilities and the possibility of catching superimposed parasitic and other infections. Being in self-declared exile is hell! Am I being unduly paranoid? I would also consider working as a volunteer in the AIDS communities in Africa if it were safe to move from my Midwestern cocoon. My kids think that I am crazy to consider these alternatives. It has been seventeen years since presumed infection and no AIDS-defining illness but lots of medications. Any words?
A: As long as you continue to be asymptomatic, have an undetectable viral load, and a CD4 count of 350 cells/mm3, your risk of infectious complications with a trip to India are not too much higher than in a non-HIV-infected person. The most important infectious diseases that you would need to consider would be TB and bacterial (pneumococcus, meningococcus, Haemophilus influenzae, salmonella, shigella, etc). The parasitic diseases that you may be more susceptible to include cryptosporidiosis and toxoplasmosis. Both are endemic in India. If you are already toxoplasma immune, it is not an issue. You could decrease your risk by getting the following vaccines before you go to India: pneumococcus, meningococcus, typhoid (parenteral, not the live oral vaccine), hepatitis A and B. You should be meticulous about avoiding uncooked food, only drink bottled water (even for brushing teeth) and have some ciprofloxacin or doxycycline on hand for travelers' diarrhea. Finally, there are more than 4 million HIV-infected people in India. For a very small percentage of these individuals, HAART therapy and the highest standards of care are available. There are a growing number of physicians in the major Indian cities with considerable experience in the clinical management of HIV. This is to reassure you that if you travel to major cities in India, you would likely have access to well-qualified help, should you become ill.
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