9TH ANNUAL CLINICAL UPDATE FOR RYAN WHITE CARE ACT TITLE I, II, III, AND IV GRANTEES

9TH ANNUAL CLINICAL 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

• Can you offer 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

• Please discuss the mechanism of trimethoprim/sulfamethoxazole (TMP/SMX)-induced rise in creatinine, its relation to dose, and how to diagnose (ie, what elevation of creatinine or decrease in creatinine to tolerate?). TMP/SMX is very important for 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 the use of angiotension converting enzyme (ACE) inhibitors in HIV-infected patients without hypertension, who are on antiretroviral therapy with CD4+ cell counts above 500/µL for asymptomatic proteinuria?
  
  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 and 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. 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 there is evidence of neurosyphilis based on CSF findings.
  
  
• Originally, valacyclovir was not recommended for people with severe immune-suppression. 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 valacyclovir/day) has not been observed in HIV- seropositive 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