(For more on that joyous process, read this interesting debate here in the New England Journal of Medicine.)

The question seemed to have no obvious right answer, so I did what one is explicitly allowed to do in this phase of the process – in other words, I asked some experts for their advice.

As a reminder, the case is a guy with positive blood cultures for MRSA (vancomycin MIC 2.0) on hospital day 4 despite receiving vancomycin (trough 15) and having undergone resection of a mycotic aneursym on hospital day 3.

Choices were:  1) continue current vancomcyin dose; 2) increase vancomycin to achieve trough of 20; 3) change to daptomycin; 4) change to linezolid.

Expert Number One said the following:

What a terrible question.  A classic case of “what is the writer thinking and how much does he/she know?” 4 is clearly wrong, but I wouldn’t be surprised to hear that this is what they want.  If the MIC is really 2,  you need a trough of 40, which is not an option, so 2 is wrong.  Given that he is only 5 days out and average duration of bacteremia in this setting is 7 days or so, you could consider 1 with reassessment in 2 or 3 days (but this is not really given here) and with MIC of 2, probably won’t work.  That leaves 3 by default, but with MIC of 2,  there is a significant possibility of heteroresistance to bothvanco and dapto.  A terrible question.  I wouldn’t know how to guess what they want!

And Expert Number Two — who kindly allowed me to cite as Dr. Myoung-don Oh, who is the corresponding author of this paper — generously offered:

I think there are several issues to resolve.

#1. Is the patient failing on VCM therapy? I think it is too early to declare VCM failure in this case. (1)The median duration of MRSA bacteremia(or mycotic aneurysm) is >4 days (2) Even if we choose an optimum antibiotic, MRSA bacteremia would persist if infected focus is not removed). In this case, the aneurysm was resected on HD#3. Therefore, I would rather wait 2 more days to see if MRSA bacteremia persist.

#2. VCM MIC=2 can predict worse prognosis? Previous studies have shown that higher VCM MIC was associated with poor outcome. CID 2008;46:193-200; JCM 2004;42:2398-402; Arch Intern Med 2006;166:2138-44. However, I think we still need further data on this issue, because other variables, especially host conditions and site of infection, also affect the outcome.

#3. With VCM MIC=2(assume that it is confirmed by “gold standard test” rather than E-test), would you like to increase VCM dose? It seems to me that rationale for higher dose VCM is favorable AUC/MIC. Recent guideline (CID, 2009) also recommends VCM trough level of 15-20mg/L, because this gives you AUC/MIC greater than 400 in case that MIC= 1 ug/mL. Problems of this recommendation include (1) correlation between PK/PD parameters & clinical outcome still need further data, (2) increased renal toxicity, (3) AUC/MIC not achievable if VCM MIC>2. (Actually, strength of the recommendation is BIII).

# 4. How about daptomycin for this bacteremic patient? Daptomycin is non-inferior to VCM for initial therapy of MRSA bacteremia. However, if you switch to daptomycin, it’s a salvage regimen. And I am not aware of any clinical data regarding salvage therapy. As VCM MIC =2, I am afraid that cross-resistance between VCM & daptomycin might compromise this salvage therapy.

In conclusion, I’d rather wait for 2 more days with the same VCM treatment.

Which certainly made me feel better.  Since the answer the examiners wanted was daptomycin.

Just published in the journal Neurology – not typically on my radar screen — is this remarkable study comparing pregabalin to placebo for HIV-related distal sensory peripheral neuropathy.

Here are the results:

At endpoint, pregabalin and placebo showed substantial reductions in mean Numeric Pain Rating Scale (NPRS) score from baseline: -2.88 vs -2.63, p = 0.3941.
(-snip-)
Individuals with HIV-associated neuropathy achieved NPRS treatment effect size similar to those in studies of diabetic peripheral and postherpetic neuralgia. However, the placebo group in the current study had a much higher NPRS change than in the diabetic peripheral neuropathy or postherpetic neuralgia studies

In other words, the pregabalin here worked great, but the placebo effect was so gargantuan that the placebo was just as good.

Writing in Journal Watch:  AIDS Clinical Care, the always-astute Abbie Zuger has a theory why this happened:

Notably, this study is not the first in which a treatment for HIV-related peripheral neuropathy has elicited an unusually high placebo response. The reasons behind that phenomenon would be extremely interesting to pursue — might HIV-positive individuals have greater faith in the power of medication than do others?

I think she’s on to something important here.  After all, in how many other diseases can patients so directly link the medications they are taking to their own survival?

And we clinicians who practice HIV medicine should keep this in mind when prescribing medications to our patients.  Strong mutual conviction that something will work — from both provider and patient — may well be a self-fulfilling prophecy.

Why not leverage this for all it’s worth?

Man with history of IDU admitted with fever, has bacteremia due to MRSA (MIC 2 mcg/mL confirmed by E-test). Found to have mycotic aneurysm of superficial femoral artery.  Aneurysm is resected surgically on hospital day 3. On vancomycin 1 gm IV q12 hours, vancomycin trough is 15 μg/mL.  Blood cultures drawn on hospital day 4 turn positive the next day; patient is subjectively improved but still febrile. WBC has declined from 16k to 11K.

What is the best next step?

1. Continue current rx
2. Increase vancomycin dose to achieve trough of 20 mcg/mL
3. Change vancomycin to daptomycin
4. Change vancomycin to linezolid

So what’s the answer?

Does anyone really know what the best thing to do here is?  For the record, I got it “wrong.”

However, I haven’t switched anyone over from the capsules yet, and neither has anyone else in our practice.

Would be interested in hearing how it’s going so far — best news would be that the tablets are both more convenient and have fewer side effects, but we know from the switch to Kaletra tablets that the latter might not occur.

(Which surprised me, I have to admit — thought the tablets would be better tolerated, but it was about the same.)

So … if you’ve switched patients to from the capsules to the tablets, comment away!

Nothing like last year’s NA-ACCORD, or 2008’s surprising DAD study, or 2007’s raltegravir studies, to name a few recent examples.

(All subsequently published, of course — links are to the papers.)

Still, as usual, lots to think about:

• Does expanded HIV treatment reduce new infections? Maybe …
• Could the rest of the country expand HIV testing and linkage to care the way they have done in Washington, D.C.?  Wow, those are impressive data.
• Can a 4-drug-in-one pill treatment compete with what we have, or will have?  You decide.
• Is boosted atazanavir as good as efavirenz?  Seems so.
• What are the long-term consequences of these changes in renal function or bone health? The  extent to which our treatments accelerate aging remains a major open question.
• Is there any doubt that letting the CD4 cell count fall increases the risk of non-AIDS complications? I don’t think so.  (Multiple other papers with similar findings.)
• Is tenofovir the only drug associated with renal dysfunction?  Not according to this study.
• Could there be a (broader) role for a CCR5 antagonist?  Especially one that is once-daily and does not require boosting? This drug looks promising, but frankly I don’t see it unless a better tropism test can be worked out — or even better, if there’s some non-antiviral utility to these drugs, or (hope of hopes) they can be part of a “cure”.
• Is “intensification” dead?  Maybe not, but it’s clearly on life support.  See studies with raltegravir, maraviroc, and enfuvirtide for the evidence.

But just when we think we have it all figured out, there are these two excellent overviews of how we neither have a cure for HIV (Maldarelli) nor can we treat all our patients successfully (Eron).

These are great summaries of two remaining challenges in the field, and well-worth the web casts — which are viewable here.

But since John Mellors announced the dates of next year’s conference — and because the CROI web site can be “leisurely” in posting this information — I offer the following evidence as a public service to researchers, teachers, clinicians, and schedule-makers out there in HIV/ID Land.

Come for the conference, stay for the weather!

(I don’t suppose many people see the link between those two events.  Oh well.)

And since the “pocket program” to the Conference has been available since last week, below is a highly-subjective (admittedly developed-world centric) list of potentially important presentations, in a somewhat random order.  Apologies ahead of time for leaving off something of great importance, most likely buried somewhere deep in the poster presentations.

• 28 Immunodeficiency, HIV RNA Levels, and Risk of Non-AIDS-defining Cancers
• 30 HIV Infection Is an Independent Risk Factor for Lung Cancer
• 33 Decreases in Community Viral Load Are Associated with a Reduction in New HIV Diagnoses in San Francisco
• 34 Monitoring the Impact of Expanded HIV Testing in the District of Columbia Using Population-based HIV/AIDS Surveillance Data
• 53 Safety and Efficacy of TBR 652, a CCR5 Antagonist, in HIV-1-infected, ART-experienced, CCR5 Antagonist–Naïve Patients
• 54LB Phase 3 Trials of Vicriviroc in Treatment-experienced Subjects Demonstrate Safety but Not Significantly Superior Efficacy over Potent Background Regimens Alone
• 57 Efficacy and Safety at 48 Weeks of Once-daily vs Twice-daily DRV/r in Treatment-experienced HIV-1+ Patients with No DRV Resistance-associated Mutations: The ODIN Trial
• 58LB Single-tablet, Fixed-dose Regimen of Elvitegravir/Emtricitabine/Tenofovir Disoproxil Fumarate/GS-9350 Achieves a High Rate of Virologic Suppression and GS-9350 Is an Effective Booster
• 59LB ACTG 5202: Final Results of ABC/3TC or TDF/FTC with either EFV or ATV/r in Treatment-naïve HIVinfected Patients*
• 74 RV 144 Update: Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thai Adults
• 87LB PRO2000 Vaginal Gel is Ineffective in Preventing HIV Infection: Results of the MDP301 Phase III Microbicide Trial
• 88LB Association of Expanded HAART Coverage with a Decrease in New HIV Diagnoses, Particularly among Injection Drug Users in British Columbia, Canada
• 101LB Raltegravir Intensification in Antiretroviral-treated Patients Exhibiting a Suboptimal CD4+ T Cell Response
• 106LB Bone and Limb Fat Outcomes of ACTG A5224s, a Substudy of ACTG A5202: A Prospective, Randomized, Partially Blinded Phase III Trial of ABC/3TC or TDF/FTC with EFV or ATV/r for Initial Treatment of HIV-1 Infection*
• 107LB Chronic Kidney Disease and Exposure to ART in a Large Cohort with Long-term Follow-up: TheEuroSIDA Study
• 125 Rapid Progression of Atherosclerosis at the Carotid Bifurcation Is Linked to Inflammation in HIV-infected Patients
• 128 Higher and Increasing Rates of Fracture among HIV-infected Persons in the HIV Outpatient Study Compared to the General US Population, 1994 to 2008
• 129 HIV Infection and Fragility Fracture Risk among Male Veterans
• 134 A Finite Course of ART during Early HIV-1 Infection Modestly Delays Need for Subsequent ART Initiation:ACTG A5217, the SETPOINT Study
• 135LB Profound Depletion of HIV-1 Transcriptionally Active PBMC by Early cART during Primary HIV-1 Infection but Not by Treatment during Chronic Infection: Results of the Zurich Primary HIV Infection Study
• 136 ART and Risk of Heterosexual HIV-1 Transmission in HIV-1 Serodiscordant African Couples: A Multinational Prospective Study
• 153LB Efficacy of ART with NVP+TDF/FTC vs LPV/r+TDF/FTC among Antiretroviral-naïve Women in Africa: OCTANE Trial 2/ACTG A5208
• 263  Longer Phase I Viral Decay in Treatment-naïve Patients Receiving Raltegravir-based ART: Preliminary Results from ACTG 5248
• 285 Maraviroc Intensification for Suboptimal CD4+ Cell ResponseDespite Sustained Virologic Suppression: ACTG 5256
• 476 Strong Effect of Early ART during Primary HIV-1 Infection in Preventing further Spread of HIV in Sexually Active Men Having Sex with Men
• 510 A One-pill, Once-daily Fixed-dose Combination of Efavirenz, Emcitrabine, and Tenofovir Disoproxil Fumarate Regimen Is Associated with Higher Unannounced Pill Count Adherence than Non-one-pill, Once-daily Regimens
• 526 Life Expectancy of Recently Diagnosed Asymptomatic HIV-infected Patients Approaches that of Uninfected Individuals
• 527 Time with CD4 Cell Count above 500 cells/mm3 Allows HIV-infected Men, but Not Women, to Reach Similar Mortality Rates to Those of the General Population: A 7-year Analysis
• 983 CD4 at HAART Initiation Predicts Long-term CD4 Responses and Mortality from AIDS and Non-AIDS Causes in the HIV Outpatient Study
• 503 Episodes of HIV Viremia and the Risk of Non-AIDS Events among Successfully Treated Patients
• 504 Persistent Low-level Viremia Is Associated with Increased Risk of Virologic Failure and Mortality
• 505 Association between Low-level Viremia below 50 Copies/mL and Risk of Virologic Rebound in HIV-infected Patients Receiving HAART
• 508 Relative Effectiveness of Preferred Initial Antiretroviral Regimens in the CFAR Network of Integrated Clinical Systems Cohort
• 509 Early ART Compared to Deferred ART during Acute Opportunistic Infection Leads to a Reduction in the Systemic Inflammatory Response Resulting in Improved Immunologic Outcomes
• 707 Earlier Initiation of ART in HIV-infected Individuals Is Associated with Reduced Arterial Stiffness
• 708 Inflammation Is Associated with Endothelial Dysfunction among Individuals with Treated and Suppressed HIV Infection
• 714 Incomplete Immune Recovery on HAART Is Associated with Significantly More Cardiovascular Events and a Trend Towards More Non-AIDS-related Malignancies in Dutch ATHENA Cohort
• 716 Abacavir Induces Human Leukocyte Endothelial Cell Interactions
• 717 Abacavir, a Competitive Inhibitor of Soluble Guanylyl Cyclase, Increases Platelet Reactivity
• 718 Changes in Cardiovascular Biomarkers with Abacavir: A Randomized, 96-week Trial
• 720 Metabolic Profiles and Body Composition Changes in Treatment-naïve HIV-infected Patients Treated with Raltegravir 400 mg Twice-daily vs Efavirenz 600 mg Each Bedtime Combination Therapy: 96-week Follow-up
• 427 Does cART with Greater CNS Penetration Prevent the Development of CNS Opportunistic Diseases?
• 429 Higher CD4 Nadir Is Associated with Reduced Rates of HIV-associated Neurocognitive Disorders in the CHARTER Study: Potential Implications for Early Treatment Initiation
• 734 Low CD4 Cell Count and Impaired Renal Function Are Independent Risk Factors for ARF in HIV-infected Patients
• 735 HAART Is Associated with Improved Kidney Function in Patients with Impaired Kidney Function at Baseline but Was Associated with Slight Worsening of Kidney Function in Patients with Normal Baseline Kidney Function
• 723 A 48-week Randomized Study of Uridine Supplementation vs Switch to TDF on Limb Fat, Mitochondrial Function, Inflammation, and Bone Mineral Density in HIV Lipoatrophy
• 725 Inflammation and Mortality in HIV-infected Adults: Analysis of the FRAM Study Cohort
• 740 Predictors for Change in Estimated Glomerular Filtration Rate in HIV-infected Individuals with or without cART: The Swiss HIV Cohort Study
• 742 Genetic Variants of ABCC10 Are Associated with Kidney Tubular Dysfunction in Patients Treated with Tenofovircontaining Regimens
• 746 Longitudinal Analysis of Bone Mineral Density in Aging Men with or at Risk for HIV Infection
• 748 Bone Turnover, and in Particular Osteoclast Activity, Is Increased in Patients with Confirmed Proximal Renal Tubulopathy within the Swiss HIV Cohort Study
• 750 Assessment of Vitamin D Levels among HIV-infected Personsin the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy: SUN Study
• 752 High Prevalence of Severe Vitamin D Deficiency in cARTnaïve and Successfully Treated Swiss HIV Patients
• 554 Resistance-associated Mutations to Integrase Inhibitor S/GSK1349572 in HIV-1 Integrase Inhibitor-naïve and Raltegravir-experienced Patients
• 580 Prevalence of Transmitted Antiretroviral Drug Resistance among Newly-diagnosed HIV-1-infected Persons, US, 2007
• 581 Prevalence of Mutations Associated with Transmitted Drug Resistant HIV among BED Recent Versus Long-term Infections, US, 2006
• 585 Decreasing Prevalence of Drug Resistance Mutations over a 7 Year Period in the CFAR Network of Integrated Clinical Systems
• 594 Early Switch Based on Virological Failure Reduces Complexity of HIV-1 Drug Resistance

(*Disclosure:  I’m a co-author on these presentations.)

On February 10, 2010, FDA approved Norvir (ritonavir) 100 mg Tablets. These tablets do not require refrigeration.  Unlike the capsule formulation [pictured], Norvir tablets must be taken with meals.
–snip–
NORVIR tablets are not bioequivalent to NORVIR capsules. Under moderate fat conditions (857 kcal; 31% fat, 13% protein, 56% carbohydrates), when a single 100 mg NORVIR dose was administered as a tablet compared with a capsule, AUC_{(0- ∞)} met equivalence criteria but mean C_max was increased by 26% (92.8% confidence intervals: ↑15 -↑39%).

This is obviously an advance — the Norvir soft-gel capsule is much-despised for a variety of reasons, one of the most notable being the glob of melted capsules that results if the medication is left in the car, in a warm room in the summertime, near a radiator, etc.  When Kaletra switched from capsule to tablet, the heat-stability was a big improvement in convenience, and also made treatment in resource-limited settings much easier.

Time will tell if the increase in peak levels has any effect on tolerability, a potential concern since much of ritonavir’s toxicity is dose-related.   I suspect Abbott will have both formulations available for a while until this is sorted out.

And for those who still have patients still on 600 mg twice-daily — it’s time to switch to something else!

Over on our Journal Watch/AIDS Clinical Care web site, we’ve posted case of a pregnant woman who says she’s taking ART as prescribed, but the lab tests say otherwise.

How do you manage these cases?

Non-cirrhotic portal hypertension (portal hypertension that is not caused by cirrhosis of the liver) is rare in the United States. It occurs when blood flow in the major vein in the liver (the portal vein) slows down.
–snip–
Because of the potential severity of portal hypertension, including death from hemorrhaging esophageal varices, FDA has revised the Warning and Precautions section of the didanosine drug label to assure safe use of the medication.

Yes, this is a bad one — of the 42 reported cases, 4 patients died; several others required aggressive interventions to reduce the risk of variceal bleeding, including banding/ligation of esophageal varices, transjugular intrahepatic portosystemic shunts (TIPPS),  and liver transplantation.

ddI was our second approved antiretroviral, way back in 1991.

Over the years, it has improved — we’ve reduced the dose, now can give it once daily, and have gotten rid of the original bizarre formulation (pictured).

And while it does have reasonable antiviral potency (at least for an NRTI), its myriad potentially severe side effects — neuropathy, pancreatitis, lactic acidosis, to name a few — and the availability of numerous other options mean that there is little reason for a person to be receiving it today.