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Primary Care Corner with Geoffrey Modest MD: 1 shot of penicillin for early syphilis in HIV patients??

13 Apr, 17 | by gmodest

by Dr Geoffrey Modest

2 articles of note just came out on syphilis.

MMWR presented data on rates of primary and secondary syphilis in the US in 2015 (see https://www.cdc.gov/mmwr/volumes/66/wr/mm6613a1.htm ). The overall case rate was 7.5/100K population, nearly 4 times the previous lowest documented rate of 2.1/100K in the year 2000, a nadir after which it has increased each year. The rate increased 22% during 2011-13.

Details:

— in 2015, there were 23,872 reported primary and secondary syphilis cases in the United States.

— 81.7% of male primary and secondary syphilis cases were among gay, bisexual, and other men who have sex with men (MSM)

— among the 44 states reporting information on the sex of sex partners for > 70% of male cases, the rates were:

— overall for men over 18 years old: 17.5/100K

— men who have sex only with women: 2.9/100K

— MSM: 309.0/100K, which translates to:

106.0 times the rate among men who have sex with women only, varying by states from 39.2-342.1 times

— 167.5 times the rate among women

— the highest rates of primary and secondary syphilis among MSM were in the South and West, the top 5 being in North Carolina (peaking at 748/100K), Mississippi, Louisiana, South Carolina, and New Mexico

—  the highest rates of primary and secondary syphilis overall were in Louisiana, California, North Carolina, Nevada, Florida, Arizona, Oregon, Maryland, Illinois, and Mississippi.

— As a point of historical reference, the lowest state specific MSM primary and secondary syphilis rate in 2015 was 73.1/100K in Alaska, surpassing the highest overall US primary and secondary syphilis rates in 1946, at 70.9/100K

— this analysis was limited by a few issues: only 44 states had the sex of sex partners reported for >70% of male cases; the number of MSM in each state was estimated based on surveys and there may be significant underestimation; and the incidence of syphilis infections may be underreported.

 

—————————————————–

Another article looked at 1-dose versus 3-dose regimens of intramuscular benzathine penicillin for early syphilis in patients with HIV (See DOI: 10.1093/cid/ciw862).

Details:

— 64 patients were randomized to 2.4 million versus 7.2 million units of intramuscular benzathine penicillin for early syphilis (2.4 million units every week for 3 weeks). The study was from 2009-2013.

–mean age 35, 95% male, 84% MSM, 58% African-American/31% Hispanic/11% white, 6% primary syphilis/61% secondary/33% early latent, 59% had had syphilis before, mean CD4=388/64% on HAART, 49% of those on HAART had undetectable viral loads

— primary syphilis was defined as having compatible genital, anal, or oropharyngeal ulcers; secondary syphilis if they had skin rash or mucosal lesions.  Those with positive serologies (all had positive RPR as well as the more specific TP-PA, T pallidum particle agglutination) were classified as early latent syphilis if they had a documented negative result followed by a positive within 12 months, or at least 4-fold increase in RPR titer.

— median RPR at baseline was 1:128

— RPR and symptoms were monitored every 3 months, and treatment success was defined as at least a fourfold (2 dilution) decrease in RPR during 12 month follow-up.

Results:

— only 9 of the 64 patients had seroconversion (negative RPR after treatment), 4 in the 1-shot and 5 in the 3-shot groups

— intention to treat analysis: treatment success rate was 80% in single-dose versus 93% in 3-dose regimens, absolute difference 13%, but not statistically significant.

— Per protocol analysis: success rates were 93% with single-dose and 100% with 3-dose regimens, also not statistically significant.

— no difference by CD4 counts (< 350 vs >350), HIV viral load, use of HAART at baseline, RPR at baseline (<32 vs >=32), or syphilis stage

— only 1 of 20 (5%) patients with undetectable HIV viral load did not achieve treatment success ; whereas 8 of 44 with detectable HIV did not achieve treatment success, a non-significant difference, but there were 6 in the 1-shot group and 2 in the 3-shot group.

— no severe reactions (eg Jarisch-Herxheimer), and none developed neurologic symptoms during the follow-up period.

— They conclude that the current CDC recommendations for a single-dose of benzathine penicillin is reasonable for HIV-infected patients with early syphilis

Commentary:

— the historic concern here was that:

–Treponema pallidum was and is quite susceptible to penicillin

–essentially all adults with early syphilis have their RPR revert to normal after treatment with 2.4 million units of benzocaine penicillin, i.e. a single dose

— but, in those with HIV infection, about one third do not serorevert.

–there seemed to be a higher rate of abnormal CSF findings as well as clinical neurosyphilis in HIV-positive people at earlier stages of syphilis infection (these data predated  HAART therapies).

— However, clinical failure after 1-shot treatment was actually quite rare, though I saw a report of at least one HIV-infected patient who had progression to neurosyphilis after 2.4 M units of benzathine penicillin for early syphilis infection.

–so, many of us, myself included, automatically prescribed 3 weekly doses, or 7.2 million units. However subsequent data on seroreversion were not much better with this higher dose.

 

–is this study generalizable? And should we just follow the CDC guidelines (ie 1-shot of 2.4 million units of benzathine penicillin)?  There are a few issues:

–really small numbers of patients overall, so above study was underpowered to detect clinically significant differences

–overall a pretty healthy group from CD4 perspective. They did comment that of the 17 patients with CD4 <200 at the time of the syphilis diagnosis, all 11 with 1-shot and 5 of 6 with 3 shots had appropriate serologic response

–but the questions remain: does this apply to those who are more immunocompromized (eg a patient with CD4=50)? or those with detectable viral loads (there was difference noted above, though not statistically significant in this small study)? Does short-term followup of the surrogate marker of RPR titers necessarily correspond to clinical efficacy in the longer-term? Could some of these patients (perhaps with lower CD4 counts) still infect others while their RPR more slowly responds? Should we look at CSF findings (perhaps a better marker of neurosyphilis) and potential long-term neurologic outcomes instead of RPR?

 

So, my conclusions from this study:

— the big conclusion is that syphilis is increasing in MSM around the country, meaning that people seem to be less protected from the spread of other sexually-transmitted infections as well (eg HIV). And the syphilis/HIV coinfection rates are quite high: reported rates of 15.8% in Los Angeles and up to 47.4% in Philadelphia. Sounds like a potential public health (and individual) disaster waiting to happen…

— in terms of the appropriate treatment for syphilis, my guess is that the CDC guidelines are reasonable. But, given the dearth of clear data, my inclination would still be to use 7.2 million units (3 shots) in those more severely immunocompromised (eg CD4 under 200 or so ????, even more so if nonsuppressed HIV viral load). Would be great to have a larger study with more varied patients (different CD4 counts, viral loads, longer term followup including clinical outcomes, etc)

Primary Care Corner with Geoffrey Modest MD: Meningococcal vaccine in HIV-positive patients

15 Nov, 16 | by EBM

By Dr. Geoffrey Modest

There are 2 potentially very serious bacterial infections, both with functional vaccines available but not previously recommended, that seem to be more common in HIV infected patients: HIB (haemophilus influenzae type B) and meningococcus. The Advisory Committee on Immunization Practices, ACIP,  just came out with recommendations to immunize HIV-positive patients against meningococcus.

Details:

  1. For the HIB infection: I had been immunizing all HIV patients with HIB vaccine until a few years ago, based on a case-control study about 20 years ago showing a higher prevalence of invasive HIB infections in HIV positive patients. Though the data on efficacy were lacking, it seemed to me that the potential benefit far outweighed the very low risk of this tried-and-true vaccine. The current feeling, from my reading, is that while HIV may be a risk factor for invasive HIB infections, the incidence of HIB infections overall has plummeted due to the aggressive HIB immunizations of children, dramatically decreasing the HIB reservoir and shifting the serotype of prevalent H flu infections dramatically away from typable to nontypables. So, it does seems unnecessary to immunize. But, it still may still be reasonable to vaccinate those patients who come from and return to countries without universal pediatric HIB immunization.
  1. Meningococcal vaccine: I also began immunizing my HIV patients with meningococcal conjugate vaccine several years ago, after the outbreak of meningococcal disease in HIV-positive people in New York, though I stopped a couple years ago because of strong and persistent statements by the CDC not to do so. The new recommendations, however, are that all HIV-infected persons be immunized pretty aggressively (see https://www.cdc.gov/mmwr/volumes/65/wr/mm6543a3.htm?s_cid=mm6543a3_x ).
  • Those < 2 years old should get MenACWY-CRM (Menveo) at 2, 4, 6, and 12-15 months, or get MenACWY-D (Menactra) at ages 9-23 months and then 12 weeks later (with the caveats that this last one be given: only if >4 weeks after finishing the pneumococcal conjugate vaccine and either before or concomitantly with DTaP — see below)
  • Those > 2 years old and not previously vaccinated should get a 2-dose primary series of the conjugate vaccine (either of the above), 8-12 weeks apart
  • Those who had most recent vaccine dose < age 7 years should get a booster 3 years later, then every 5 years thereafter
  • Those who had most recent vaccine dose > age 7 years should get a booster 5 years later, and every 5 years throughout life.
  • The immunogenicity study (comparing a single vs a series of 2 vaccines in patients with CD4 percent>15%) noted serious adverse events in 2.2-6.5% six weeks post-vaccination, the number of adverse events being inversely related to CD4 percent, and only one of the serious adverse events (ocular pain) felt to be related to MenACWY-D. A study in kids aged 2-10 found 5% had a serious adverse event, but none felt to be attributable to the vaccine
  • Overall, from a lifetime perspective, vaccination was calculated to lead to the prevention of approx 122 cases of meningococcal disease and 23 deaths, and 385 quality-adjusted life years (QALY) could be saved, with mean cost of $732,000 per QALY if the primary series of vaccines and lifelong boosters every 5 years were given.

Commentary:

  • The risk of meningococcal infection in HIV patients, from data from the US, UK, and South Africa, is 5-13x that of non-HIV infected, with prevalence of 3.6-6.6 per 100,000, and with a case-fatality rate that is a bit mixed: those with HIV in South Africa had about twice the meningococcal case fatality rate (20% vs 11%), though this was not found in New York or the UK.
  • The risk of meningococcal disease is higher in those with high viral loads or low CD4 counts, though the immunogenicity of the vaccine is about 50% lower in those with lower CD4 counts (i.e., better to wait until the CD4 increases in those with uncontrolled infections, though unclear exactly what the cut-point here is from the studies. The one study the MMWR quoted used the CD4 cutpoint of 200 from a New York study, finding a 5.3-fold increased risk with CD4<200). Similar risk in men and women.
  • The majority of meningococcal infections in HIV-infected people are of serogroups A,C,W, and Y. One issue is that the largest database, the passive National Notifiable Diseases Surveillance System, does not include HIV status. The Active Bacterial Core surveillance (ABCs), a smaller database from 10 sites and representing 14% of the US population, does include HIV status. Based on these somewhat limited data, there were 62 cases of meningococcal disease in HIV-infected patients from 1995-2015, 13% were serogroup B and 10% were of unknown serotypes; 92% of cases were in people aged 20-59 years old
  • They do note that the only licensed vaccine for those >55 years old is the meningococcal polysaccharide vaccine; they still recommend the MenACWY conjugate vaccine, based on limited data.
  • The recommendations for infants 2-23 months are complex: they recommend the MenACWY-CRM and not the MenACWY-D because of potential immune interference with the PCV conjugate vaccine with the latter, as well as potential interference of DTaP with MenACWY-D if the MenACWY-D was given 30 days after the DTaP, but not if the 2 are given simultaneously or if the MenACWY-D is given first
  • Ndata on efficacy or adverse events if meningococcal vaccine given during pregnancy or lactation
  • So, the bottom line for me: I do plan to restart giving HIB vaccine to HIV-infected patients who are going back and forth to countries without routine HIB vaccination for kids (not CDC recommended, but makes sense to me). in addition, i will adopt the meningococcal conjugate vaccine according to the ACIP schedule above, including the booster immunization every 5 years, though i will wait until the CD4 increases to a level of >15% or until it plateaus at its highest CD4 percent (using the CD4 percent, as in the studies they quoted: there was no mention of the absolute CD4 count). I will also wait until the viral load is suppressed, since the limited data found a better response if the viral load was lower, in one of the studies if <400. The CDC does not mention anything about meningococcal serogroup B vaccination, but i would consider using the meningococcal B vaccine if there were a local outbreak of serogroup B infections (though my literature search revealed nothing on the immunogenicity or efficacy of that vaccine in HIV-positive patients).

Primary Care Corner with Geoffrey Modest MD: HIV Drug Costs and Effectiveness. Are We Going in the Wrong Direction?

8 Nov, 16 | by EBM

By Dr. Geoffrey Modest

An observational cohort study looked at patients on antiretroviral therapy (ART) for HIV, finding that some of the most effective yet cheapest regimens are not being recommended for use today (see Eaton EF. AIDS 2016; 30: 2215). I have included the 340b pharmacy pricing, which is the reduced federal pricing available since 1992 to eligible health care organizations (mostly Federally-funded clinics and public hospitals) vs the AWP, average wholesale price, used in private pharmacies.

Details:

  • 491 patients (mean age 36, 83% men, 61% African-American) initiating anti-retroviral therapy (ART) between 2007-2013, at the University of Alabama at Birmingham
  • Durability (time from regimen initiation to discontinuation), used as a surrogate for the combo of effectiveness and tolerability.
  • Results for the 5 most common ART regimens used during that time:
    • TDF/FTC (tenofovir disoproxil fumarate/emtricitabine) with efavirenz (atripla): durability 40.1 months; 340b price $726.26
    • TDF/FTC with raltegravir: durability 47.8 months (longest); 340b price $1080.60
    • TDF/FTC with darunavir/ritonavir: durability 47.8 months (longest); 340b price $1153.00
    • TDF/FTC with atazanavir/ritonavir: durability 31.9 months (shortest); 340b price $1070.88
    • TDF/FTC with rilpivirine: durability 3 months; 340b price $917.50
  • Overall, combining durability with price, the efavirenz (atripla) regimen dominated, with the rilpivirine one following closely behind

Commentary:

  • Several of the older treatments have been downgraded in recent guidelines, including atripla (TDF/FTC/EFV) for neuropsych effects of dizziness, anxiety, lack of concentration, vivid dreams and suicidality (though large observational studies have not found increased suicidality) and complera (TDF/FTC/rilpivirine) since it is less effective in those with high HIV viral loads.
  • The new guidelines do attach a comment that we should consider cost in determining the regimen, but they formally downgraded the cheapest regimens. For a review of the guidelines, see http://blogs.bmj.com/ebm/2016/07/29/primary-care-corner-with-geoffrey-modest-md-2016-hiv-treatment-guidelines/ for the Intl Antiviral Society–USA guidelines, or go to https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf for the DHHS updated guidelines (these 2 do differ slightly, with the first one suggesting the TAF (tenofovir alafenamide) regimens only, but the first-line regimens are basically the most expensive of the list below)
  • I did get today’s 340b pharmacy costs for common HIV meds, for a 30-day supply (note: the 340b cost is much lower and does not track well with the AWP)
    • Atripla (TDF/FTC/EFV): $688.93 (generic is still not available, but should be soon, which should drive down this cost)
    • Truvada (TDF/FTC): $428.61 (generic is still not available, but should be soon, which should drive down this cost)
    • Raltegravir: $591.58
    • Descovy (TAF/FTC): $428.61 (ie, same price as brand-name truvada, and probably because the drug company wants us to continue with this product instead of the switching to the generic truvada when available. And though TAF does not have the long clinical trials of TDF, it does offer some real potential advantages in terms of decreasing the renal and bone toxicities of TDF)
    • Tivicay (dolutegravir): $832.44
    • Odefsey (TAF/FTC/rilpivirine): $1716.13
    • Genvoya (elvitegravir/cobicistat/TAF/FTC): $1893.68
    • Stribild (elvitegravir/cobicistat/TDF/FTC): $1638.87 (though here, substituting TAF for TDF does seem to increase the cost….)
    • Prezcobix (darunivir/cobicistat): $759.39
    • Evotaz (atazanavir/cobicistat): $700.70
    • Triumeq (dolutegravir/abacavir/3TC): $1580.35
  • Just to put all of this in perspective:
    • The new drugs are really great, with excellent acceptability (I have had to stop dolutegravir only once for GI effects), along with remarkable efficacy, combined with much more “leniency” than the older drugs such as efavirenz (one can miss more doses but maintain continued viral suppression, without developing resistance so easily)
    • But the old drugs (especially atripla) were the ones which were able to turn the AIDS from almost uniformly fatal to almost uniformly a chronic disease
    • And, the vast majority of patients tolerated these drugs well. The +/- 90%  who were able to continue on them had the same remarkable great outcomes as with the new drugs (I have rarely had to change my old patients on atripla to one of the newer formulations)
    • And, these old regimens are likely to get much cheaper when generics become available
  • So, what does this all mean? We live in an extremely expensive health care system (1/3 of Massachusetts spending is for healthcare/Medicaid), yet we have the remarkably opaque system where clinicians providing the care are “shielded” from its cost. Hospitals do not provide us with the cost of MRIs or colonoscopies, or the fact that at one hospital it is 2-3x the price of another. It is not easy to find the actual costs of medications, and this cost can vary considerably from one pharmacy to another (again, it is a lot of work for us to find out the actual costs). Drug companies and hospitals, in these cases, have no interest in advertising costs — drug companies promote the “newest and best” to us through sponsoring the studies and advertising aggressively (and expensively) to us and directly to consumers, highlighting their new cancer drug which increases life expectancy a couple of months at $100,000 per injection, etc etc. Ironically, we clinicians as consumers would (mostly, I assume) never tolerate buying other consumer products without knowing their price and their relative value compared to other items of the same class. so, though I have been prescribing these new HIV drugs to my newly diagnosed patients, I think this article really does give pause and highlights the strange situation we are in in our increasingly expensive, increasingly unaffordable, intentionally cost-opaque health care system, which in many ways does not lead to major improvements in community health or health care outcomes, yet with us as clinicians inadvertently being put in the position of how $$ is spent: a perfectly devised system to maximize the profits of the drug companies, hospitals, etc. And many of the people sitting on the committees writing the new guidelines in medicine are financially supported by drug companies, etc, both for their research and personal financial gain, which really should be seen as an unacceptable conflict-of-interest.

See http://blogs.bmj.com/ebm/2016/04/26/primary-care-corner-with-geoffrey-modest-md-life-expectancy-and-income/ , a recent blog which includes reference to the book The Health Care Paradox, which argues well that we in the US spend huge amounts of money per capita on medical care but reap really poor-to-mediocre improvements in health outcomes (e.g., infant mortality or life expectancy being lower than almost any other industrialized country), because we devote the vast majority of the medical care $$ specifically to health care and such a low percentage to public health/social programs that promote the prerequisites for good health: good employment, housing, food, supportive social environments, exercise programs, day care/elder care……)

Primary Care Corner with Geoffrey Modest MD: 2016 HIV Treatment Guidelines

29 Jul, 16 | by EBM

By Dr. Geoffrey Modest

The International Antiviral Society–USA panel just released their 2016 recommendations for antiretroviral drugs for treatment and prevention of HIV infection in adults (see Gunthard HF. JAMA 2016; 316(2): 191; and this group did include several HIV luminaries, such as Paul Sax from Brigham & Women’s and Paul Volberding from UCSF).

Summary:

  • When to initiate therapy:
    • Everyone who has detectable virus, independent of CD4 count; and as soon as possible after acute HIV infection (to reduce the latent HIV reservoir, immune activation and perhaps protection against infection of central memory T cells)
    • Also in those with persistent undetectable virus without ART (antiretroviral therapy) if declining CD4 counts, which can occur in these “elite controllers”, since they have higher levels of immune activation and increased cardiovascular risk. [I had such a patient who died in his 40s from lung cancer and minimal smoking history. Though lung cancer can occur in such patients not infected with HIV, there is a higher risk of lung cancer in HIV patients, and my guess is that his “controlled HIV” off medications played a part. Unclear if meds would have helped, however]
    • Start ART as soon as possible in patients with opportunistic infections (OIs), with the possible exceptions of cryptococcal meningitis (data from resource-limited settings showed poorer results with early treatment, though using flucytosine here seems to improve results). Need careful monitoring with active TB, esp TB meningitis, which has higher rates of immune reconstitution inflammatory syndrome (IRIS).
  • Recommended initial regimens
    • Dolutegravir/abacavir (ABC)/lamivudine (3TC)
    • Dolutegravir plus tenofovir alafenamide (TAF)/embricitaine (FTC)
    • Elvitegravir/cobistat/TAF/FTC
    • Raltegravir/TAF/FTC
    • A couple of comments:
      • They replaced TDF (tenofovir disoproxil fumarate) with TAF because of increased bone loss and renal dysfunction/proximal renal tubular toxicity with TDF. However TAF should not be used with rifamycins and there are limited data on pregnant women. And TAF may have worse lipid profiles than TDF.  But they note that TDF is basically fine to use if well-tolerated, more available in coformulation (i.e. with FTC), and potential concerns that TAF really has no long term data.
      • Only use ABC if HLA-B*5701 negative. Also still use cautiously in those with high cardiovascular risk, since a few studies have suggested an association with MI
    • All of these above regimens use InSTIs (integrase strand transfer inhibitors). suggested non-InSTI-based regimens include:
      • Darunavir (boosted with cobicistat or ritonavir) plus TAF/FTC or TDF/FTC, or ABC/3TC
      • Efavirenz/TDF/FTC (which, by the way, is generic, is associated with similar efficacy to the above regimens when patients are able to tolerate it, and would lead to a $900 million annual savings in the US over the prior branded version of Atripla -this study was done in 2012 prior to the newer ?more expensive regimens…. and efavirenz/TDF/FTC has been my go-to regimen for about 20 years and has done really, really well overall)
      • Rilpivirine/(TAF or TDF)/FTC
  • Special populations:
    • Hep B coinfected
      • Use regimen with TAF or TDF, 3TC or FTC, and a 3rd med for the HIV
    • Pregnant women
      • Treat the woman to improve her own health and decrease her likelihood of neonatal transmission
      • AZT/3TC has the longest track record, though has more toxic effects
      • Raltegravir is the recommended InSTI
      • Boosted atazanavir/r daily or darunavir/r bid are recommended PIs
      • Efavirenz is the recommended NNRTI after the 1st 8 weeks of pregnancy. Though if woman is on it before pregnancy, best to continue to maintain virologic suppression
    • Hep C coinfected
      • Use HIV meds that do not interact with Hep C virus therapies. Consult current HCV treatment guidelines
      • At this point, recommended regimens include dolutegravir/ABC/3TC; and dolutegravir or raltegravir plus TAF/FTC.
        • Specifically, would now avoid regimens with NNRTIs, boosted PIs or elvitegravir/cobicistat
      • Renal disease
        • Monitor all patients for development of kidney disease with eGFR, urinalysis, testing for glycosuria and albuminuria or proteinuria when ART initiated, changed, or every 6 months when HIV RNA is stable
        • Worst offender seems to be TDF and especially in combo with boosted PIs [for unclear reasons, they do not comment that the D:A:D study, Mocroft A Lancet HIV 2016; 3: e23 found pretty equivalent declines in eGFR with atazanavir-r and lopinavir-r as with TDF]
        • Not use or dose-adjust TDF if creatinine clearance<60
        • Not use TAF if renal function gets worse (esp proximal tubule dysfunction) or if creat clearance <30
        • Renal transplant is okay if ESRD, since high expectation of high rates of patient and graft survival [though, I should add, there are data that those with CD4<200 fare less-well, to the point that one of my patients on dialysis cannot get a renal transplant until his CD4 is consistently above 200]
      • Osteoporosis/fractures
        • Patients may lose 2-6% of bone mineral density at the hip and spine in first 1-2 years. greater initial decline with TDF-containing regimens, so avoid in osteopenicpatients
  • CD4 count and primary OI prophylaxis
    • Prior guidelines for OI prophylaxis were based on CD4 counts
    • They feel that for patients achieving viral suppression with ART, the incidence of MAC (mycobacterium avium complex) has declined so much that primary prophylaxis is not recommended, though not enough data on PCP (pneumocysitis jirovecii pneumonia) so should still use prophylaxis (see my comment below)
  • Lab monitoring (not much change):
    • The usual: initial CD4, viral load, hepatitis serologies, comprehensive metabolic panel, urinalysis, STIs, lipids. Also genotype testing for resistance.  Recheck 4-6 weeks after starting ART. Then every 3 months for a year. Then can go every 6 months for adherent patients with suppressed virus. They also suggest checking HLA B*-5701 prior to initiating ABC treatment (though I do check it routinely on initial presentation in case I need to change meds later)
    • If pretreatment CD4<200, check every 3 months until viral load reliably suppressed and CD4>350 for 1 year. Then every 6 months until virus suppressed for at least 2 years and CD4>500
    • When virus suppressed for >2 years and CD4>500, repeat monitoring of CD4 unnecessary unless virologic failure (defined as viral load >200)
    • If viral load rebounds to >50, assess for causes of virologic failure (in particular medication adherence, and food-drug interactions)and repeat in 4 weeks
    • Typically virologic suppression occurs within 24 weeks of ART initiation
    • If virologic failure, check genotype (consider proviral DNA assays to estimate archived resistance if the viral load is below 500-1000, the limits of the regular genotype assay) and change ART meds (studies mostly suggest that viral loads in the 50-200 range should be monitored more closely, since the data are inconsistent about virologic failure)
    • Can do InSTI resistance testing if patient fails therapy and has not stopped ART for >1 month.
  • Engagement in care/adherence
    • Early diagnosis is important. We should use an opt-out strategy for testing (i.e., present testing to the patient as a usual lab test, allowing for patients to actively opt out of testing)
    • Retention in care is key: 30% of new HIV infections are in people with undiagnosed infections, 60% in those not engaged in care
    • Predictors of not being engaged in care include:
      • Substance use (and methadone maintenance programs/opioid substitution therapy are great ways to retain patients in HIV care)
      • Depression
      • Directly observed treatment is helpful (as in methadone programs or other daily contacts with patients)
    • Patient navigators and care coordinators help
  • Prevention (not much change):
    • Treatment as prevention is primary strategy
    • Pre-exposure prophylaxis (PrEP), especially if population has HIV incidence >2%/yr. can be daily TDF/FTC (which they prefer) or intermittent (see blogs below)
    • Immunize against hep A,B. Check for STIs. Follow at least every 3 months
    • Post-exposure prophylaxis as soon as possible after exposure (prior to test results, and within 72 hours per most guidelines). Use TDF/FTC plus raltegravir bid or dolutegravir daily and continue 28 days. Check HIV serologies at 4-6 weeks, 3 months, and 6 months later. Can also use TDF/FTC plus boosted darunavir or TDF/FTC/cobicstat/elvitegravir

Commentary:

  • In terms of OI prophylaxis, I’m not sure I’m ready to stop MAC prophylaxis based just on viral suppression. I have seen a few patients on long-term ART with consistent viral suppression but who maintain very low CD4 counts (on the order of 50). The data supporting not using MAC prophylaxis is from a small study (see Yangco BG. AIDS Patient Care STDS 2014; 28(6): 280) of 41 patients eligible for MAC prophylaxis by CD4 count but not on it, put on ART with subsequent viral loads <1000, and finding no MAC infections. BUT, this was an observational study; of the only 11 MAC infections in the overall cohort (n=369), the infections happened 43-126 days after starting ART; and there are no data on how their CD4 counts changed after 1-2 months on therapy (i.e., did these patients remain below the 50 cells/mL level while on therapy???). The paper’s conclusion was “primary MAC prophylaxis may not be required for virologically suppressed patients with CD4<50 cells/ml”.  So, out of caution and without a clear study, I personally would still keep patients on prophylaxis until their CD4 counts increase sufficiently (>50).
  • A still unanswered and not so uncommon situation is immunologic failure: patients who continue to have viral suppression but have deterioration of their CD4 counts. I have had several patients with this, and my very anecdotal experience is that patients have a pretty sustained increase in CD4 when I have added/switched to dolutegravir.
  • So, this guideline reflects the fact that the treatment of HIV infection has been transformed more rapidly and dramatically than any treatment I have seen. It has gone from a disease with essentially 100% mortality, despite taking >30 pills/day with meds up to every 4-5 hours throughout the day and night, and lots of adverse reactions, to an essentially 100% treatable disease with 1 pill a day and no adverse reactions. In fact HIV infection is now much easier to treat than hypertension and much much easier than diabetes…

 

See:

http://blogs.bmj.com/ebm/2015/12/23/primary-care-corner-with-geoffrey-modest-md-hiv-therapy-without-nrtis/ for a blog on HIV therapy without NRTIs, in those intolerant or resistant

http://blogs.bmj.com/ebm/2015/10/05/primary-care-corner-with-geoffrey-modest-md-hiv-pre-exposure-prophylaxis/ for a blog on the PROUD trail of daily TDF/FTC as PrEP

http://blogs.bmj.com/ebm/2015/12/18/primary-care-corner-with-geoffrey-modest-md-on-demand-hiv-pre-exposure-prophylaxis/ for the IPERGAY trial of on-demand TDF/FTC PrEP

Primary Care Corner with Geoffrey Modest MD: Pap Smears Post-Hysterectomy in HIV Positive Women

18 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A rather striking retrospective study was just published from 2 clinics in Texas, showing a high rate of vaginal intraepithelial neoplasia (VAIN) and vaginal cancer in HIV-infected women with no prior history of abnormal cytologic screening and who had a hysterectomy for conditions other than cervical dysplasia and cancer (see Smeltzer S. Obstet Gynecol 2016; 128: 52).

Details:

  • 68 providers, 4 of whom did regular pap screening, with 1827 HIV-positive women seen in 2015. Rate of pap testing was 47%
  • 238 women were seen between 2000-2015 with a history of HIV, previous hysterectomy, and no previous abnormal Pap test results
  • Median follow-up time for the Pap test was 16 years.
  • Results:
    • 164 (69%) had normal Pap test results
    • 12 (5%) had results showing atypical cells of undermined significance and human papillomavirus-positive
    • 55 (23.1%) had results showing low-grade squamous intraepithelial lesion
    • 7 (2.9%) had results showing high-grade squamous intraepithelial lesion
    • Of those who underwent biopsy for abnormal pap tests:
      • 15 (28%) had normal results
      • 23 (43%) had VAIN 1
      • 9 (16%) had VAIN 2
      • 7 (13%) had VAIN 3
      • No patients had invasive vaginal cancer.
    • No demographic risk factor was associated with the abnormal Pap test results after hysterectomy (race, smoking history, alcohol history, illegal drug use). Also no association with a specific indication for the hysterectomy (fibroids vs pelvic pain vs bleeding). The story was mixed on HIV-related risk factor (though overall there was not much difference in CD4 or viral load between those with normal vs abnormal paps, within 6 months of the pap abnormalities there was a significant deterioration: median CD4 was 573 vs 364, and viral load was 248 vs 400, all values with p<0.001)
    • Older patients and higher viral load significantly increased the risk of development of an abnormal Pap test result. For example, the patients with viral load values greater than 400 had approximately two times the risk of developing an abnormal Pap test result than those lower than 400; the adjusted hazard ratio of 2.1 (95% CI 1.2–3.5). In terms of age: 30-38yo HR 2.2, 38-44yo HR 3.8, >44yo HR 6.3
    • No difference in time to abnormal Pap test result was noted with antiretroviral use, or by CD4.

Commentary:

  • No guidelines suggest regular pap screening for women with a hysterectomy, unless the hysterectomy was done for cancer or precancerous lesions
    • USPSTF, Am Cancer Society, ACOG, etc are against routine screening in these women overall:  “The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (cervical intraepithelial neoplasia [CIN] grade 2 or 3) or cervical cancer”, giving it a “D” recommendation
      • However, I should add that old studies did find a non-zero but low risk of vaginal abnormalities in women in the general population getting a pap smear post-hysterectomy for benign causes (see Pearce KF. N Engl J Med 1996; 335: 1559, which noted that of 9610 vaginal smears, atypical squamous cells of undetermined significance (ASCUS) occurred in 52 (0.5%); low-grade squamous intraepithelial lesion in 44 (0.5%); high-grade squamous intraepithelial lesion in 6 (0.1%); and squamous-cell carcinoma in 2 (0.02%). In 5 women, biopsies revealed vaginal intraepithelial neoplasia type I or II; there were no biopsy-proved cases of vaginal cancer. The probability of an abnormal Pap smear in this group of women was 1.1 percent, and the positive predictive value of the Pap test for detecting vaginal cancer was 0.Mean time to get potentially significant intraepithelial lesions was 19 yrs. Because of the age of this study, there was no information about HIV or HPV status.
    • There are very limited data and no clear recommendations on pap testing in HIV-positive women having a hysterectomy for benign reasons.
  • There are several unanswered questions (which really should be studied).
    • This Texas study was a retrospective analysis with limited data collected and there are no data I’ve seen on the effect of interventions on changing actual clinical outcomes in abnormalities picked up by routine screening
    • We know that HPV infection tends to persist in HIV-positive men and women, with attendant increased risk of anal and cervical cancers. It would be great if there were prospective data looking at HPV status and vaginal paps in women. In the above study, the ASCUS findings were associated with HPV. My guess is that HPV is the culprit and that it seems reasonable to consider HPV and/or pap screening in women with HPV infection at the time of hysterectomy and later if at risk for getting an HPV infection. But this should be studied. And it is really important that we pursue HPV vaccination rigorously in young women (and men).
      • Since there was a deterioration of HIV markers (CD4 and viral load) within 6 months of the abnormal pap, perhaps should we be doing selective paps on those with HIV deterioration, or at certain levels of these counts. Again, it would be good to know prospectively if changes in HIV markers consistently preceded vaginal cytology abnormalities.
      • This study was done in a single population/demographic area. Is it generalizable?
      • Is there any relationship between numbers of sexual partners, partners infected with HIV, etc. and the development of VAIN?
    • So, this study does throw a bit of a wrench into conventional wisdom. It is pretty clear that there is more of a risk for vaginal cytologic abnormalities in women with HIV who get a hysterectomy for benign reasons than we had thought, and that recommendations be reconsidered given the relatively benign test (pap), and further work-up (biopsy). To me, it is not unreasonable to assume that for a woman with significant abnormalities on vaginal biopsy and with pathological deterioration on observation/local therapy, that definitive therapy be considered.
    • But, at this point, it does seem reasonable to do vaginal pap smears on women with HIV and hysterectomy for benign reasons. Unclear what interval. But it seems from the data that these are not very aggressive or rapidly progressive evolution from VAIN to cancer, so likely that they could be done every several years.

Primary Care Corner with Geoffrey Modest MD: Urine-Based Rapid TB Test

12 Apr, 16 | by EBM

By Dr. Geoffrey Modest

The lancet just reported a study looking at a rapid, low-cost urine test to guide TB treatment in HIV-positive individuals in areas with high TB prevalence (see Lancet 2016; 387: 1187).

Background:

  • TB is the leading cause of death in people with HIV, accounting for 360K deaths in 2013; post-mortem analysis in resource-limited countries find that TB is the cause of death in about 40% of HIV-infected people, in 85% of cases it is disseminated, and half are undiagnosed at the time of death
  • Those with HIV have a higher case-fatality rate when co-infected with TB: increased disseminated extra-pulmonary TB, more severe TB as immunocompromise increases.
  • It is harder to diagnose TB in those with advanced immunosuppression, since they often have low bacillary loads in their bodily fluids, reducing the sensitivity of smears and cultures
  • ​There is a urine test detecting the lipoarabinomannan Ag (LAM), a glycolipid antigen of the M tuberculosis cell wall, which reflects hematogenously disseminated TB. It requires 60 ml of urine, takes 25 minutes to get a result, and costs $2.66/test. It has a specificity of approx 94% and a sensitivity of around 56% in a meta-analysis. but, compared to sputum-smear microscopy, it does identify patients with the most severe illness

Details of study:

  • 2659 patients (median age 37, 51% female, CD4 of 84, 48% on antiretroviral therapy (ART) at time of hospitalization, 73% on ART by 8-week follow-up) in 10 hospitals in Africa (South Africa, Tanzania, Zambia, Zimbabwe) were randomly assigned to urinary LAM testing, with 2528 ultimately in the modified intention-to-treat analysis
  • 8-week mortality was 578 (23%)
    • 261 (21%) in the LAM group and 317 (25%) in the no LAM group, an absolute reduction of 4% (1-7%) and relative risk reduction of 17% [RR 0.83 (0.73-0.96, p=0.012]
  • Overall sensitivity of LAM was 45.6%, specificity was 88.7%, positive likelihood ratio of 4.03, negative likelihood ratio of 0.61
  • But for those with CD4 ≤50, sensitivity of LAM was 63.7%, specificity was 83.2%, positive likelihood ratio of 3.80, negative likelihood ratio of 0.44; and 46% of the deaths happened in those with CD4 ≤50
  • The overall % of patients begun on antiTB therapy was much higher in the LAM group (55% on day 1 and up to 91% on day 8) vs those without LAM (40% on day 1 and up to 89% on day 8), p=0.024 for difference.
  • In the subgroup of patients with CD4 ≤​50, LAM reduced mortality by 29%
  • The attending clinicians delayed TB therapy in the no LAM group because they favored a different diagnosis (e.g. bacterial pneumonia), or they were waiting for the results of diagnostic investigations.

Of note, a recent concern has developed with the spread of MDR-TB (multiply drug-resistant) in Daru Island in New Guinea, with a commentary in Lancet Respiratory Medicine (see http://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(16)00101-6.pdf ). The spread of TB, especially resistant TB, is referred to as a “time bomb”. And, of rather concerning note, TB is not so common in Daru and most patients with MDR have never taken TB meds (i.e., they did not develop resistance by taking meds, but were infected with a very difficult-to-treat TB infection), and lots of people there got infected (200 people in this 6 km2 island with only 15,000 individuals, i.e., about 1% of the population). This scary outbreak “will almost certainly eclipse those of both the Ebola and the recent Zika virus outbreaks, deemed a global public health emergency, combined”, per the Lancet commentary.

So, I bring up this LAM study for several reasons:

  • It seems pretty likely to me that TB really is a ticking time-bomb, and reading this article on LAM is a reality check on this
  • TB tends to have the highest morbidity and mortality in resource-poor countries, which have to deal with an array of very expensive and urgent other issues (little things like famine, war, etc.). A couple of days ago the NY Times ran a very concerning article on Vietnam (see http://www.nytimes.com/2016/03/29/health/vietnam-tuberculosis.html​ ), a country with a remarkably effective TB program (90% cure rate for uncomplicated TB, 75% in drug-resistant cases — with a global average is 50%), where improving outcomes further is getting more expensive (needing to do more outreach into rural areas, finding/treating those addicted to heroin…), but their hospital wards are packed (with more potential to lead to spread of MDR) and their “money is close to running out”
  • TB has the potential to develop highly virulent strains, and the above article on New Guinea is shocking at how virulent a multi-drug resistant TB can be (and MDR, of course, is associated with much more cost to control as well as an inherently higher mortality). And the risk of worldwide spread of a virulent and less-treatable TB is much increased as travel becomes easier and more frequent
  • We are continually dealing with outbreaks of newer, potentially devastating diseases (e.g., Zika, Chikungunya, Ebola,…) which divert attention and resources from staid old TB
  • And LAM really may be a huge benefit in resource-limited countries, where AIDS-related deaths are still very high (i.e., AIDS has not evolved into a chronic disease requiring taking one pill to control, as in the US and many resource-rich countries), and LAM is a cheap and easy test to identify and treat those with likely imminent death
  • But even in the US, TB infection in HIV has been increasing, with increasing numbers of observed vs expected cases (see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3122491/​ ), noting that the increase in cases in US cities is both from reactivation of latent TB by HIV-related immunocompromise, but that 41% were due to recent transmission
  • Now, one might argue that there should just be empiric anti-TB therapy in all HIV-infected patients in TB-endemic areas, given the high prevalence and mortality of HIV-TB coinfection, at least in those with more severe immunocompromise. But, empiric treatment is more complicated, more expensive, and more toxic, especially in areas of MDR, which reinforces the potential benefit of LAM as a test in those co-infected with HIV and even only a remote possibility of hematogenous TB. And, with the very real possibility of TB spreading outside of the currently endemic areas (as now shown in New Guinea), and co-infecting those with HIV, LAM may become a reasonable test in more and more countries around the world.

 

Primary Care Corner with Geoffrey Modest MD: HIV Therapy Without NRTI’s

23 Dec, 15 | by EBM

By Dr. Geoffrey Modest

The vast majority of recommended HIV drug regimens include tenofovir (TDF)/emtricitabine (FTC) or abacavir (ABC)/lamivudine (3TC) as the nucleoside/tide reverse transcriptase inhibitor (NRTI) backbone. From the 2015 HIV guidelines (see http://blogs.bmj.com/ebm/2015/04/17/primary-care-corner-with-geoffrey-modest-md-updated-hiv-guidelines-2015/ for review) ​of the 5 initial recommended regimens, all have NRTI backbones: 4 include TDF/FTC and one has ABC/3TC. Similarly, of the 2 NNRTI-based (non-nucleoside reverse transcriptase inhibitor) and 4 PI-based (protease inhibitor) alternative regimen options, 5 have TDF/FTC and 1 has ABC/3TC as the backbone; and of the “other regimen options”, 5 have either ABC/3TC or TDF/FTC. For those “who cannot have TDF or ABC”, there is only one which is NRTI-free: darunavir/ritonavir (DRV/r) plus raltegravir (RAL), with the caveat not to use if the HIV viral load is >100K copies/ml. For treatment-experienced patients, they recommend at least 2 and preferably 3 fully active agents. They comment that a boosted PI plus an INSTI (integrase strand transfer inhibitor) may be a viable option in patients with no INSTI resistance​, as the only mention of an NRTI-free regimen. So, almost all of the studies and recommendations include an NRTI backbone. In this light, there was a recent article looking specifically at the efficacy of NRTI-free regimens in treatment-experienced patients failing therapy (See Ann Intern Med. 2015;163:908-917).

Details:

  • 360 people (26% women, median age 46, 32% white/41%black/23% hispanic, 80% with HIV viral load <50K, median CD4 of 207, 47% with AIDS) who were treatment-experienced with HIV infections and had viral resistance (though 66% were sensitive to TDF, 30% to 3TC, 29% to FTC, 40% to AZT, 49% to ABC) from 2008-2011. All had been on PI-based therapy and had either used or were found to be resistant to some NRTIs and NNRTIs.
  • Put on open-label optimized regimens not including NRTIs, based on treatment history and resistance testing, then were randomized to adding or omitting NRTIs.
  • For the optimized regimens, they assessed the cPSS (continuous phenotypic susceptibility) score, a research tool to measure antiretroviral activity, making sure it was greater than 2 (this score is the sum of the scores of the individual agents used, where a score of “1” signified that the HIV was susceptible to the drug, “0” if resistant, and the continuum from 0-1 if there were partial resistance, reflecting the degree of resistance from the upper limit of “non-resistant” to the lower-limit of “resistant” — see their Appendix Table 1 for details).
  • 93% completed a 48-week visit

Results:

  • ​The optimized regimens turned out to be: RAL (raltegravir)+DRV/r(darunavir/ritonavir)+ETR (etravirine) in 56%; RAL+DRV/r+MVC (maraviroc) in 14%, and about 8% each to RAL+DRV/r+ETR+MVC, RAL+ETR+MVC, RAL+DRV/r+ETR+ENF (enfuvirtide), or other
  • ​The added NRTI mix was 81% TDF+(3TC or FTC); 14% TDF+(3TC or FTC)+AZT; 6% other
  • Cumulative probability of treatment failure was:
    • 8% in the omit-NRTI group vs 25.9% in the add-NRTI group (nonsignificant)
    • No difference in  primary safety endpoints or % of people achieving HIV viral load <50 copies/ml
    • No deaths in the omit-NRTI group vs 7 in the add-NRTI one
  • Conclusion was that it’s okay to omit NRTIs in these patients starting a new optimized regimen, thereby reducing pill burden, cost, and toxicities.

So, this is a useful article for patients either with broad HIV resistance to NRTIs, or to patients who are intolerant of them (and I have had one treatment-naive patient who pretty clearly developed a neuropathy to 3TC, thereby eliminating virtually​ all of the current and past recommended initial therapies). The basic approach in the past was to include NRTIs, even if there were resistance (e.g., continuing the pressure of 3TC on the virus in patients resistant to 3TC selected a less-fit and less-aggressive virus). This article shows that with our newer and better and easier-to-take and tolerate regimens, there is no compelling reason to add an NRTI-based backbone, even though a pretty good % of the patients in this study were in fact not resistant to them.

Primary Care Corner With Geoffrey Modest MD: New HIV-1 Drug Approved by FDA

17 Nov, 15 | by EBM

By Dr. Geoffrey Modest

The FDA just approved a new single pill for the treatment of HIV-1. Genvoya (the new drug) is basically the same drug as Stribild (elvitegravir 150mg, cobicistat 150mg, emtricitabine 200mg and tenofovir disoproxil fumarate, or TDF,  300mg), but changes the TDF to tenofovir alafenamide 10mg (TAF). This is really a good evolution, since data over the last few years has confirmed that TAF has similar antiviral efficacy to TDF but much less renal toxicity and bone loss. The current FDA approval is for HIV-1 patients who are treatment-naive, over 12 years old, weighing more than 35 kg, as well as for adults with suppressed viral loads (<50 copies/ml) on a stable antiretroviral regimen. TAF has a much lower tenofovir dose than TDF, has lower blood levels, but higher intracellular levels (where the HIV-1 replicates). There is an accompanying boxed-warning that it can cause lactic acidosis and severe hepatomegaly with steatotosis, either of which can be fatal, and that it is not approved to treat hepatitis B infection. Common side effect is nausea. Genvoya is not recommended for patients with severe renal impairment (undefined), though can be used in those with moderate renal impairment. The European Union also approved its use in September. For the full but brief FDA press release, see http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471300.htm​ .

A couple of comments:

  • Though the FDA warned against using Genvoya for hepatitis B, there are actually some small studies finding TAF is as good as TDF for treating hepatitis B (see Journal of Hepatology, 2015-03-01, Volume 62, Issue 3, Pages 533-540).  I.e., my guess is that they mean that we should not use Genvoya for sole hepatitis B infections, though it does sound reasonable to me to use Genvoya for those with a combo of HIV and hepatitis B (as I have been doing with prior HIV regimens that have TDF/FTC as a component). But I would follow the hepatitis B viral load closely, just to be sure.
  • My understanding is that the FDA approval was based on a few studies, including a non-inferiority study just released in the Lancet Infectious Diseases journal. There they looked at 1443 patients who were on one of 4 TDF-based regimens, were virologically suppressed, and had eGFR >50 ml/min, then randomized them to either the combo of elvitegravir/cobicistat/emtricitabine/TAF (i.e. Genvoya) vs continuing their prior meds (seeorg/10.1016/S1473-3099(15)00348-5). Bottom line: at 48 weeks, viral suppression with Genvoya was 97%, vs 93% if continued their old meds. Hip and spine bone mineral density, as well as GFR and proteinuria, were better with TAF (Genvoya) than in those on the TDF-based meds, though there were more adverse events in the TAF group (mostly not related to the drug, such as URIs, with somewhat fewer Grade 3 or 4 adverse events — 9% vs 11% with TDF). Nausea was present in 5% of those on Genvoya.
  • So, finally, TAF will be hitting the approved-drug lists. Hopefully in other forms as well (e.g., just replacing the TDF in Truvada, which is TDF and emtricitabine, with TAF). We’ll see what the cost will be….​

For other blogs on tenovofir in HIV, see:

http://blogs.bmj.com/ebm/2015/04/17/primary-care-corner-with-geoffrey-modest-md-updated-hiv-guidelines-2015/ which reviews the current guidelines and highlights stribild as one of the preferred initial drugs

http://blogs.bmj.com/ebm/2015/07/23/primary-care-corner-with-geoffrey-modest-md-tenofovir-nephrotoxicity/ which comments on how best to screen for tenofovir nephrotoxicity

Primary Care Corner with Geoffrey Modest MD: Hep c 1b treatment, ribavirin-free

4 Nov, 15 | by EBM

By Dr. Geoffrey Modest

A new study highlights how rapidly the field of Hepatitis C management is progressing, moving from an interferon-free therapy to one that is now also ribavirin-free (see Gastroenterology 2015; 149: 971).

Details:

  • Open-label international study of 82 patients without cirrhosis (42 treatment-naive and 40 prior null responders) and 99 with cirrhosis (47 treatment-naive and 52 treatment-experienced with prior relapse, or a null or partial response). The demographics varied some between these different groups, but overall approx 50% male, 85% white, mean age 55, in non-cirrhotic patients –> 60% with fibrosis score F0-F1, 25% F2, 13% F3). All with genotype 1b infection. 68-95% had non-CC IL28B genotype (this may not be clinically relevant, but this genotype did portend a less favorable response to perinterferon/ribavirin treatment).
  • Treated with ombitasvir 25mg (a NS5A replication complex inhibitor), paritaprevir 150mg (an NS3/4A protease inhibitor), and ritonavir 100mg once daily for 12 weeks (if no cirrhosis) or 24 weeks (with cirrhosis). [Note: This is the same combo in the pill Viekira, minus dabasuvir 250mg]
  • Primary endpoint: sustained viral response at 12 weeks after the end of treatment (SVR12)

Results:

  • Without cirrhosis: treatment-naive had SVR12 of 95.2%, null responders had SVR12 of 90.0%
  • ​With cirrhosis: treatment-naive had SVR12 of 97.9%, treatment-experienced had SVR12 of 96.2%
  • Virologic relapse happened in 3 null responders without cirrhosis and 1 with cirrhosis
  • Virologic breakthrough occurred in 1 null responder without cirrhosis
  • ​Adverse events (varied by assigned group) included headache (17-33%), asthenia (5-21%), pruritis (0-17%), and diarrhea (0-15%). Almost all were “mild”. Serious adverse effects in 7 patients (1 each): extrusion of penile prosthesis, COPD exacerbation, esophageal variceal hemorrhage, humerus fracture and partial seizures, elevate ALT and AST levels (this patient stopped drugs for days 20-36, but then was able to resume and had an SVR12), peripheral artery aneurysm and hepatic neoplasm. Only one patient discontinued meds because of an adverse effect (isolated peripheral edema which resolved after study drug cessation)
  • One interesting sideline of the study: there were detectable RAVs (resistance-associated variants), mostly to NS5A (17.6%) as well as NS3 (1.1%). but there was no association between these baseline RAVs and response to therapy (though all 4 of those with virologic relapse and the 1 with virologic breakthrough did have RAVs in both NS3 and NS5A at the time of failure)

So, what does this all mean?  There are evolving therapies which are working on larger groups of people (treatment-naive or not, cirrhotic or not), which seem to have high barrier to clinical resistance, and with fewer meds causing adverse effects (ribavirin in this case). The landscape is changing quickly, and there is increasing hope of developing an interferon and ribavirin-free, pangenotypic, single pill therapy (at least this is much more likely than developing a reasonable-cost therapy). And, as with HIV treatment, the newer regimens are simpler, more effective, and have many fewer adverse effects. Which means that we in primary care are in increasingly good positions to take care of patients with these infections as part of taking care of the whole patient.

Primary Care Corner with Geoffrey Modest MD: HIV Pre-exposure Prophylaxis

5 Oct, 15 | by EBM

By Dr. Geoffrey Modest

A British open-labeled study looked at the effectiveness of pre-exposure prophylaxis (PrEP) to prevent HIV-1 infection in high risk patients (see doi.org/10.1016/S0140-6736(15)00056-2) — the PROUD trial, a partially drug-company funded. Details of study:

  • 544 patients enrolled (median age 35, 81% white, 5% asian, 4% black; 59% with university degree; 63% with sexually-transmitted infection (STI) diagnosed in prior year, 3 negative tests in past year), all HIV-1 negative men who had sex with men (MSM) and had anal intercourse without a condom in the previous 90 days, recruited from 13 sexual health clinics in England
  • Patients were assigned either to immediate treatment with daily tenofovir disoproxil fumarate (TDF) 245mg plus emtricitabine (FTC) 200mg, or the same treatment delayed for 1 year
  • Results:
    • 3 HIV infection in the immediate group, (1.2/100 person-years)
    • 20 HIV infections in the deferred group (9.0/100 person-years), despite being given counseling, condoms, and even 174 prescriptions for post-exposure prophylaxis (recommended dose: 28 days of TDF-FTC plus lopinivir)
    • So, relative risk reduction of 86% (64-96%, p=0.0001), absolute difference 7.8/100 person-yrs (4.3-11.3), which translates to treating 13 men for 1 year to avert 1 HIV infection
    • 21 (8%) of patients on the meds interrupted or missed doses because of 28 adverse events, 13 considered related to the study drug, almost all of which were considered mild to moderate. 3 had high creatinine levels.
    • No difference in other STIs, including rectal gonorrhea or chlamydia (which suggests that there is not much risk compensation: i.e., when those on meds think they are protected and engage in even riskier sexual practices. Also there were no reported differences in numbers of different anal sex partners between the groups, though there was more receptive anal sex without a condom in the immediate treatment group)
    • Study was stopped early because of the increase in HIV infections, and all in the deferred group were offered PrEP
    • Tenofovir was detected in the plasma of all 52 sampled participants who reported they were taking the drug.

The perspective here is that HIV infections have been increasing in the MSM community in the UK, despite increased HIV testing and earlier treatment (which decreases transmission). The PROUD trial was actually a pilot trial designed to look at recruitment and retention of patients to test the feasibility of a larger trial, but there were so many HIV infections that they could assess the effectiveness of PrEP (as a secondary outcome). Of note, the 3 cases of HIV in the PrEP group were: one with a reactive HIV test at the 4-week visit, with infection likely to have predated the PrEP; one had HIV detected at the 61st week visit but had no prescribed drug after the first 30-day supply; one seroconverted at 53 weeks, with his last clinic attendance at the 12-week visit where he got 90 days of drugs — so, all 3 were not on meds when they got HIV (meaning that no infections happened in those actually taking the PrEP). And, not surprisingly, none developed any HIV mutations (since they were not taking the drugs). 2 patients who had likely prior HIV infection did develop the codon 184 mutation, likely related to exposure to FTC. No TDF mutations were found. One interesting side issue in a non-placebo controlled trial is that patients may be more adherent to the meds, since they know they are real meds and not potentially placebo, and in that way may actually simulate the real-world clinical situation better. Also, though this should not be an issue, the formulation of TDF/FTC they used is a little different from ours, where there are 300mg of TDF.

So, a pretty remarkable study, finding that in a “real-world setting”, not in a controlled clinical trial, there was overall remarkably good medication adherence and it really worked in preventing HIV infection in this very high-risk cohort (with numbers surpassing some studies done in the ivory towers – e.g. the much larger IPrEX trial with 2499 people randomized to TDF-FTC or placebo, found a 44% reduction in HIV infections (New Engl J Med 2010; 363:2587-2599). Another option remains intermittent PrEP. The IPERGAY study (see http://www.cdc.gov/nchhstp/newsroom/2015/IPERGAY-2015-Media-Statement.html ) also found an 86% HIV risk reduction in MSM using on-demand TDF-FTC with 2 tablets taken 2-24 h prior to sex, one 24 h later and one 48 h later. It would be useful to assess the effectiveness of PrEP in other high-risk groups (e.g., drug users) in poorer communities and in other countries.

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