Welcome to the International AIDS Society-USA - 9th Annual Clinical Care Update for Ryan White CARE Act Title I, II, III, and IV Grantees

QUESTIONS FROM THE CLINICAL UPDATE
Questions submitted by participants that were not addressed at the Clinical Update are listed below with answers by the expert faculty. Additional questions-and-answers will be posted as they are available.

Complicated Antiretroviral Failure
Roy M. Gulick, MD, MPH

Advice for "weaning" a new patient off efavirenz/emtricitabine/tenofovir if he or she is intolerant.

Dr Gulick: Current empiric recommendations for stopping a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen are to stop the NNRTI first and then stop the nucleoside reverse transcriptase inhibitors (nRTIs) 1 week later. If a patient is intolerant of medications, you may not have the option of waiting to stop. In that case, you should balance the risk of recommending continuation of therapy in an intolerant patient with the risk of selecting out NNRTI (or nRTI) resistance.
If the patient is on the fixed-dose combination of efavirenz/emtricitabine/tenofovir , you should change him or her to the separate formulations of emtricitabine/tenofovir and efavirenz.

Would you substitute enfuvirtide with an integrase inhibitor as one becomes available for [a virologically suppressed] patient?

Dr Gulick: In a patient who is virologically suppressed on an enfuvirtide-containing regimen, but who wants to change the enfuvirtide (eg, because of intolerance to injection site reactions or problems giving twice-daily injections), one could consider substituting another potent agent such as an investigational or expanded access drug (ie, integrase inhibitor, CCR5 inhibitor). Although there are no study results to support this recommendation, it seems a reasonable option if the substituted agent is fully active.

You said there was no place for a structured treatment interruption (STI). There is one: For persons who were started on potent antiretroviral therapy with a high CD4+cell count (>500/mL) and were asymptomatic, and who remain suppressed.

Dr Gulick: Given recent results showing an increased (albeit low) risk of clinical events (HIV-related, death, and surprisingly, non-HIV-related) in patients who stopped antiretroviral therapy, an STI cannot be routinely recommended in any clinical setting. When considering stopping therapy, the risks and benefits of continuing versus stopping should be discussed with the patient. Many patients who started therapy with CD4+ cells above 500/mL can stop therapy without significant risks (although pharmacokinetic and resistance issues should be considered when stopping a nonnucleoside reverse transcriptase inhibitor (NNRTI).

Renal Disease and Toxicities: Issues for HIV Providers
Derek M. Fine, MD

Would you please discuss the mechanism of trimethoprim/sulfamethoxazole (TMP/SMX)-induced rise in creatinine and relation to dose and how to diagnose (ie, what elevation of creatinine or decrease in creatinine to tolerate?)? TMP/SMX is very important to use in many patients.

Dr Fine: TMP/SMX may inhibit secretion of creatinine and thereby cause an increase in the level. This is usually not a problem at the doses we use for Pneumocystis jiroveci pneumonia (PCP) prophylaxis or even the doses we use to treat urinary tract infections. At high doses for PCP treatment, there may be a small increase related to this effect, but if this is the reason, it will then plateau. The greater concern with TMP/SMX is acute interstitial nephritis, in which case the creatinine will not plateau and will continue to increase (sometimes slowly). There is no absolute cut-off, but if the creatinine increases by more than 0.2 to 0.3 mg/dL, I would be concerned. The other concern with a high dose of TMP/SMX is hyperkalemia, which results from the inhibition of sodium transport in the distal nephron by the trimethoprim component.
What about use of angiotension converting enzyme (ACE) inhibitors in patients without hypertension for asymptomatic proteinuria in HIV-infected patients on antiretroviral therapy with CD4+ cell counts above 500/µL?

Dr Fine: I would use an ACE inhibitor or angiotension-receptor blocker in such patients if their blood pressure tolerates it. Start with a very low dose and titrate up as tolerated.
Is there a predictive difference between protein:creatinine ratio and albumin:creatinine ratio? Can you disregard an elevated urine microalbumin level if the albumin:creatinine ratio is normal?

Dr Fine: The albumin:creatinine ratio is usually about 60% of the total protein:creatinine ratio. I think the protein:creatinine ratio is the more important value, as it corrects for urinary dilution:concentration that may affect the microalbumin concentration.
What is the effect of furosemide on tenofovir?

Dr Fine: I have not heard of any direct effect though they both use the organic anion transporter, OAT1, at the apical membrane of the proximal tubule. I have not seen any data that suggest competition at that site, but I am not sure it has been studied. The main concern would be that of overdiuresis with compromise in glomerular filtration rate (GFR), which would then predispose to tenofovir toxicity.
Is urine microalbumin okay to use for proteinuria screening?

Dr Fine: Yes, as long as it is an albumin:creatinine ratio (usually it is reported as such) and not just albumin concentration.
We have seen 3 cases of renal-cell cancer in our HIV patients. Have there been any reports of renal-cell carcinoma associated with HIV infection?

Dr Fine: I have not heard of this but found this reference: Baynham SA et al, AIDS Patient Care STDS, 1997. Most renal-cell carcinomas are found incidentally these days. One wonders if we are just imaging HIV patients more often and therefore finding more cases.
I have seen increased renal disease in patients who are injection-drug users. Would you comment on injection-drug use as a risk factor for renal disease?

Dr Fine: I have seen the same and believe you may be seeing this particularly in those who use cocaine. I think that drug use should be considered a risk factor for kidney disease. A good reference on this topic is: Jaffe JA et al, Clin J Am Soc Nephrol, 2006.
Do low-grade elevations of creatinine cause severe osteopenia in HIV-infected patients? And if the creatinine is corrected, will the osteopenia also improve?
Dr Fine: The renal osteodystrophy (from secondary hyperparathyroidism) is usually seen when the GFR goes below 60 mg/dL. This can be reversed with calcium and vitamin D management. Osteopenia itself is not directly associated with elevations in creatinine unless it is through this mechanism.

Below the Belt and Above the Radar: Recognition nad Management of Syphilis and Genital Herpes in HIV-Infected Persons
Connie L. Celum, MD, MPH

We were always taught to do lumbar puncture for RPR above 1:64 regardless of symptoms. But our clinics lack the funds to do the spinal taps. Can we safely treat without lumbar puncture?

Dr Celum: Ideally, if the clinic cannot be reimbursed, can these patients be referred to another center/neurologist for LPs? If not, then the patient should be carefully monitored for a 4-fold drop in titer, and if the titer has not dropped 4-fold within 3 to 6 months, he or she should have a spinal tap so that you can decide about higher dose PCN if the re is evidence of neurosyphilis based on CSF findings.
Originally valacyclovir was not recommended for people with severe immune-suppression, although it was suggested as an alternative for the man with a CD4+ count of 40/uL [in Case 2 of your presentation]. Have the recommendations changed?

Dr Celum: The data support using valacyclovir at lower doses, as typically are used for HSV-2 in HIV- seropositive persons since the thrombocytopenia observed with very high doses (up to 8 g v alacyclovir/day) has not been observed in HIV- sero positive persons treated with the usual doses of 1 g (eg , 500 mg bid) for HSV-2.

Optimizing Hepatitis B Treatment in HIV-Infected Persons
Chloe L. Thio, MD

I have a HIV/hepatitis B virus (HBV)-coinfected patient, not being treated for HIV, on entecavir 1 mg qd for 6 months. The liver function test (LFT) value is 5-times the upper limit of normal and the patient is asymptomatic, but concerned about LFT elevation. The patient is HBeAG+, and the HBV DNA level was 71 billion copies/mL prior to treatment; it is 2000 copies/mL. What do we do? Lower the dose? Stop treatment (stopping treatment may cause hepatitis flare)?

Dr. Thio: There are many causes for LFT elevations in the HIV/HBV- coinfected patient, including acute hepatitis A or C virus infection, drug use, alcohol, medications (herbal, prescription, and over-the-counter such as acetaminophen), HIV-related opportunistic infections, or HBV causes. Given that the patient probably has a high CD4+ cell count, the HIV-related causes are less likely. HBV-related causes of LFT flares include increased immune response and possible HBeAg seroconversion, natural flares of the disease, and emergence of drug-resistant HBV. As the HBV DNA level decreases, the T-cell response to HBV can increase and flares can occur. This sometimes heralds HBeAg seroconversion.
For now, I would continue the patient on the medication and watch symptoms and the LFTs closely. I would also follow HBeAg and anti-HBe to see if HBeAg seroconversion is occuring.
If drug-resistant variants are emerging then the HBV DNA should go up and you will know that is the case. Drug-resistant variants are unlikely with entecavir after only 6 months of treatment.
If a patient is HBVcAB+ only, do you need to give vaccine for Hep B?

Dr Thio: This is a difficult question since no data exist to answer it. Individuals with an isolated anti-HBc either have a false-positive test or have a prior infection with levels of anti-HBs below the limit of detection or perhaps levels of HBsAg below the limit of detection. Of course, they could also be in the window period after an acute infection, but I assume this is not the case here. My approach to these patients is to re-test their hepatitis B serological panel in 6 months to see if they are still atni-HBc+ only. If so, I would get a HBV DNA since they may have a mutated HBsAg that is not detected by the assay. If their HBV DNA is undetectable (<200 copies/mL), then I go ahead and vaccinate them.

Resistance is Futile Without a Resistance Test: Case-Based Panel Discussion
Michael S. Saag, MD

Please elaborate why zidovudine plus tenofovir (with an NNRTI) would be your choice in the presence of virus with the K65R mutation.

Dr Saag: The drugs interact in a ‘synergistic’ fashion when this mutation is present. K65R is a mutation that reduces viral susceptibility to tenofovir but increases the susceptibility to zidovudine. The mechanism for this is complicated, and has to do with ‘on’ and ‘off’ rates of the drug being added to the growing cDNA chain by reverse transcriptase. The net effect of the interaction is that the combination of tenofovir and zidovudine works well when used together in that setting.
If you have $900 to spend on an uninsured patient initially, who in chronically infected (not less than 1 year), would you spend $500 of it on a genotype?

Dr Saag: The answer is yes based on long-term outcomes. For example, if the patient had a baseline resistance mutation to either lamivudine (or emtricitabine) or efavirenz up front, and I started a regimen with these 2 drugs the regimen would not likely lead to the patient achieving the target HIV-1 RNA of below 50 copies/mL. I would have wasted the cost of a drug that did not work plus I put the patient at risk for accumulation of additional resistance conferring mutations while she or he was taking a suboptimal regimen. If the prevalence of baseline resistance mutations in your area is more than 2% to 3 % (and it is at this point in most regions of the United States and Europe), it is clearly cost effective in the long run to spend the up front money on a baseline genotype.
Would you change the regimen in a patient on lamivudine/another nRTI/nelfinavir, who is tolerating the regimen and has viral load below detection, to a regimen with a boosted protease inhibitor or efavirenz?

Dr Saag: No. If the patient has a HIV-1 RNA value below 50 copies/mL, is tolerating the regimen, and is ‘happy’ with it, I would keep her/him on that regimen.
How do you factor in the possibility of undetected viral resistance when initiating antiretroviral therapy?

Dr Saag: I assume this question is referring to the possibility of subdetectable clones of resistant virus that are not detectable by standard genotypic assays. In this setting it is highly unlikely that a patient who was never treated previously and was infected with a resistant virus has reverted completely back to ‘wild-type’, and thereby harbors low levels of resistant virus that would be missed by the resistant test. In other words, I don’t worry about it.
How reliable is a genotype test for a patient who has an HIV-1 RNA level of 1500 copies/mL.

Dr Saag: Very reliable. The issue with requiring a minimum HIV-1 RNA level of 750 to 1000 copies/mL to order a resistance test is based on the difficulty of having enough virus in the plasma to allow polymerase chain reaction (PCR) amplification of virus. Once the viral RNA is successfully amplified the test is very reliable. It usually requires at least 1000 copies/mL of virus to reliably be able to amplify the viral RNA. So a value of 1500 copies/mL should be no problem.
Some guidelines recommend HAART for patients with HIV-1 RNA levels above 100,000 copies/ml of plasma. What do you do in a patient who is asymptomatic and has a CD4+ cell count above 350/uL but has this viral load level? What are the data to support initiation of antiretroviral therapy in these patients?

Dr Saag: Assuming the patient is genuinely asymptomatic I usually do not start antiretroviral therapy until the CD4+ count has reached a level of 350 to 400 cells/uL. If the CD4+ count is higher and the patient has a very high HIV RNA I will have the patient have his / her CD4 count checked more often (eg, every 2 months) for a while to gain a sense of the rate of decline (typically the decay of CD4+ count is faster when the viral load is high). Another value I use is the CD4+ percent. If the viral load is high and the CD4+ count is close to the 350 to 400 cells/

Immunizations for HIV-Infected Patients: Indications, Timing, and Response
David H. Spach, MD

What about administration of live vaccine to household members of HIV-seropositive individuals (other than polio vaccine)?

Dr Spach: This is a complicated issue with relatively little guidance from any of the national guidelines. The major issue is that one has to weigh the risk of a susceptibly household member transmitting a vaccine strain of virus to their HIV-infected household contact versus the risk of the household member acquiring the natural virus and then transmitting it. Each of the vaccines needs to be considered individually. The recommendation for the varicella virus vaccine is vague—the product information states that vaccine recipients should attempt to avoid close association with high-risk individuals (such as immunocompromised individuals) for up to 6 weeks. If contact is unavoidable, then the risk of transmitting the vaccine virus should be weighed against the risk of acquiring and transmitting natural varicella virus. The measles, mumps, and rubella (MMR) vaccine is recommended for close contacts in order to immunize them so they will not acquire natural mumps, measles, or rubella virus and then pass on to an HIV-infected household member. Regarding live attenuated influenza vaccine, the current US Food and Drug Administration recommendation and product information state that if a household contact receives the live attenuated influenza vaccine, they should avoid close contact (eg, within the same household) with anyone with a weakened immune system for at least 21 days after receiving the vaccine. The situation with live influenza vaccine, however, is different than with other live vaccines, since there is a killed virus alternative and household members can easily be immunized with the killed vaccine that would not pose a risk to HIV-infected household members.
In a patient with a CD4+ count less than 100 cells/uL and a viral load above 100,000 copies/mL would you revaccinate for influenza in January if the first vaccine is given in October?

Dr Spach: The short answer is no. There are no recommendations to do give 2 immunizations in the same season and from a practical standpoint most vaccine supplies would be depleted by January.
- David H. Spach, MD
Will the recommendation for human papillomavirus (HPV) vaccination be expanded to include boys? Men? What is your thought about anal squamous cell carcinoma in men and whether an HPV vaccine could prevent this?

Dr Spach: There is currently no US Food and Drug Administration approval to give this vaccine to boys or men, mainly because inadequate data exist in males, not because of lack of interest. There are 2 reasons why HPV vaccination will likely eventually be expanded to include boys. First, if the goal for women is to prevent them from acquiring the HPV types that are most commonly associated with cervical cancer, then it would make tremendous sense to vaccinate boys and thus try and minimize the infection rates in the males who would be transmitting the virus to women. Second, since about 80% of anal cancers are caused by types of HPV that are in the vaccine, yes, the vaccine should be able to significantly reduce the rates of anal cancer in men if they receive the vaccine as boys (before they are infected with the types of HPV associated with anal caner). Accordingly, if all boys were vaccinated against HPV, it would subsequently reduce the risk of anal cancer in those young men who subsequently engage in male-to-male anal sex. Fortunately, there are ongoing HPV vaccine studies in males. As to the benefit in vaccinating adult women or adult men, this is more controversial since many adults would have already been infected with HPV—in essence, for many, the horse is already out of the barn. No question, the greatest benefit will be to vaccinate all individuals prior to the onset of their sexual activity. Nevertheless, HPV vaccine still there still might end having a role in adults if it prevents develop of strains that a person has not already acquired or if it is ever shown to impact the progression from infection to development of cancer (by upregulating immune control of HPV).

New Drugs, New Regimens, New Outcomes
Joseph J. Eron, Jr, MD

Will be using entry inhibitors with enfuvirtide?

Dr Eron: The possibility of synergy between entry inhibitors is an exciting one. In vitro, their are data that suggest synergy between several pairs of entry inhibitors. Clinical data are forthcoming.
Will clinical test [sic] be needed/available to test for tropism when maraviroc becomes available?

Dr Eron: There is an agreement between the makers of maraviroc (Pfizer) and Monogram Biosciences to make the test available.

HIV Infection in Women: From Perinatal Issues to Vaccine
Carmen D. Zorrilla, MD

We have been receiving many conflicting responses re: PAP smears in HIV+ women with hysterectomies. If there is no cervix, is a vaginal swab recommended on an annual basis?

Dr Zorrilla: A Pap smear can detect abnormalities in the whole genital tract including tubes and ovaries when the uterus is present. The sensitivity and specificity are low, so it is not used as a screening tool for those tissues/organs. When the uterus is removed (ie, by hysterectomy) the Pap smear will be used to evaluate cells from the vagina. Patients with cervical cancers who undergo hysterectomies have routine vaginal smears. I would make a parallel with women living with HIV since they are at high risk of developing dysplasias in all of the genital tract not only the cervix. Some of these women actually undergo hysterectomies for "premalignant lesions" and they should be having periodic vaginal smears. Anecdotally I have seen 3 women with prior hysterectomies who present with abnormal pap smears and vaginal dysplasias. There is no published info to my knowledge about the sensitivity of the Pap for the other areas. So, I would continue the surveillance based on the CD4 + cell count (annually if the count is above 500 /uL and every 6 months if it is below 500 /uL).