Zoledronate Protects HIV Positive Men against Bone Loss for at Least 5 Years

This is groundbreaking 

Two doses sustain increases in bone density past 5 years (plus calcium and vitamin D)

http://www.hivandhepatitis.com/hiv-related-conditions/hiv-bone-loss-osteoporosis/3542-zoledronate-protects-hiv-positive-men-against-bone-loss-for-at-least-5-years

Merck’s Cavalier Attitude Towards the Welfare of HIV/HCV Coinfected Patients

What You Don’t Know, You Can Sell

tagline Spring 2012<http://www.treatmentactiongroup.org/tagline/2012/spring/tagline/2012/spring>



by Tracy Swan

In places where access to antiretroviral therapy is widespread, people
living with HIV are now dying from a common and curable coinfection:
hepatitis C virus (HCV). HIV increases the risk for, and accelerates the
rate of, liver disease from hepatitis C. Pegylated interferon and
ribavirin, medications used to treat HCV, are less effective in people with
HIV than in their HCV-monoinfected counterparts.

In 2011, the first hepatitis C protease inhibitors, Merck’s boceprevir and
Vertex’s telaprevir, were approved based on trials in people with hepatitis
C monoinfection. Both drugs are being studied in coinfected people, thanks
to pressure from the international HIV/HCV community and encouragement from
regulatory agencies.

Despite outrage from activists, Merck refused to study drug-drug
interactions (DDIs) between boceprevir (Victrelis), their HCV protease
inhibitor, and drugs commonly used to treat HIV, putting coinfected study
volunteers at risk for drug-drug interactions in their own clinical trial.

Drug-drug interactions can have serious consequences for HIV/HCV-coinfected
people, who risk forfeiting current and future treatment options for HIV
and possibly HCV as well. DDIs can lower drug concentrations to an
ineffective level, leading to drug resistance, or increase drug
concentrations, worsening side effects and leading to treatment
discontinuation; they can even be life-threatening, as was the case with
ribavirin and didanosine (DDI; Videx).

The boceprevir coinfection study opened in mid-2009, before Merck had
performed drug-drug interaction studies with HIV protease inhibitors in
healthy volunteers, a common step in drug development. Nonetheless,
coinfected study volunteers were allowed to use them; in fact, by default,
HIV protease inhibitors— or Merck’s own integrase inhibitor, raltegravir
(Isentress)—were the only HIV treatment options for study volunteers, since
non-nucleoside reverse transcriptase inhibitors were not allowed. Activists
kept asking Merck to perform DDIs throughout boceprevir’s development, but
Merck’s attitude remained cavalier; they did not launch key drug-drug
interaction studies until two years later, months after boceprevir was
approved.

The results of DDI studies with three ritonavir-boosted HIV protease
inhibitors, atazanavir/r (Reyataz), darunavir/r (Prezista), and lopinavir/r
(Kaletra) in healthy volunteers (rather than the actual trial participants
who were using boceprevir with HIV protease drugs for almost a year) were
presented in March at the 19th Conference on Retroviruses and Opportunistic
Infections (CROI) in Seattle. The news was not good. Combining boceprevir
with these HIV protease inhibitors lowered concentrations of each HIV
protease inhibitor, at both the highest and lowest (peak and trough) levels.

Boceprevir lowered the peak concentration of atazanavir/r by 25 percent,
and the trough by 49 percent; darunavir/r peak decreased by 36 percent and
trough by 59 percent; for lopinavir/r, coadministration with boceprevir
dropped the peak concentration by 30 percent and trough by 43 percent. In
turn, boceprevir levels dropped by 45 percent when coadministered with
lopinavir/r and by 32 percent when administered with daruanvir/r; only
atazanavir/r had no effect on the concentration of boceprevir.

Failure to characterize these drug-drug interactions put study
participants—and coinfected patients— at an unacceptable level of risk,
although clinical implications—or real-life impact on HIV and hepatitis C
treatment outcomes—of these drug interactions are not clear. Nonetheless,
the U.S. Food and Drug Administration warned that “drug interactions
between the hepatitis C virus (HCV) protease inhibitor Victrelis
(boceprevir) and certain ritonavir-boosted human immunodeficiency virus
(HIV) protease inhibitors (atazanavir, lopinavir, darunavir) can
potentially reduce the effectiveness of these medicines when they are used
together.”

Regulators from the European Medicines Agency’s (EMA) Committee for
Medicinal Products for Human Use (CHMP) went a step further, recommending
that “doctors treating patients co-infected with hepatitis C and HIV should
be aware of the findings of the drug interaction study. They should not
co-administer Victrelis with ritonavir-boosted darunavir or lopinavir in
HIV and hepatitis C co-infected patients. Co-administration of Victrelis
with ritonavir-boosted atazanavir may be considered on a case-by-case basis
if deemed necessary in patients with suppressed HIV viral loads and with an
HIV strain without any suspected resistance to the HIV regimen. Increased
clinical and laboratory monitoring is warranted.”

Vertex’s rival protease inhibitor, telaprevir (Incivek) has outsold
boceprevir: in the fourth quarter of 2011, telaprevir trounced boceprevir
$456.8 million to $87 million. The opportunity to capture the coinfection
market share may have motivated Merck’s decision to delay drug-drug
interaction studies. HCV is more likely to be diagnosed and treated in
HIV-positive people than people with HCV alone, for several reasons. HIV
treatment guidelines recommend HCV testing for all HIV-positive people; the
infrastructure to deliver treatment is already in place; and hepatitis C is
known to be more aggressive in people with HIV, so physicians and patients
are more game to try for a cure.

After Vertex reported drug interactions between telaprevir and ritonavir
boosted HIV protease inhibitors, boceprevir became a more attractive option
for co-infected people. Merck’s vice president of clinical research, Robin
Issacs, alluded to off-label use in the company’s February 8 press release.
“Though VICTRELIS is not indicated for the treatment of chronic HCV in
those who are also infected with HIV, we recognize that some physicians
have prescribed or may be considering prescribing VICTRELIS for patients
taking ritonavir-boosted HIV protease inhibitors. We felt it was important
to share these data as part of our commitment to patient safety and
transparency.”

*Where was Merck’s commitment to safety during boceprevir’s development? We
can only hope that no patients have been harmed.*

The boceprevir experience underscores the importance of timely DDI studies.
There are other medications used by people with hepatitis C—whether or not
they are coinfected with HIV—that warrant study, such as methadone,
buprenorphine, and commonly prescribed psychiatric medications. Merck
representatives have stated that the company will be more proactive with
their promising second-generation hepatitis C protease inhibitor, MK-5172.

Activists have released a
statement<http://www.treatmentactiongroup.org/hcv/2012/hepatitis-c-drug-development-and-drug-drug-interaction-studies>
calling
on regulatory agencies and pharmaceutical companies to study DDIs between
experimental HCV drugs that are broken down by the body in a similar way
with hormonal contraceptives, methadone, buprenorphine, lipid lowering
agents, immunosuppressive drugs, herbal remedies, and commonly prescribed
psychiatric medications in addition to HIV medications. •

Interleukin-7 is Looking Better and Better….

CROI 2012- Oral Presentation  #94:   Gut Mucosa T Lymphocyte Restoration in Chronically HIV+ Patients Treated with Recombinant Interleukin-7

HIV infection caused decreases in CD4 cells in the gut mucosa that are only partially restored by ART. This study was an open-label  study of recombinant interleukin-7 (rhIL-7) (manufactured by Cytheris) in chronically HIV-infected persons, on ART, mostly immunologic non responders with CD4 between 101 to 400 cells/mm3 and  HIV viral load <50 copies/mL. 

Twenty-two patients have been enrolled and received 3 weekly rhIL-7 injections at 20 mcg/kg. All were evaluated at baseline , and at week 12 post-IL-7 administration for peripheral blood T lymphocyte counts and plasma HIV-RNA. Gut mucosa sampling was performed.

Blood CD4 and CD8 were 260 and 650 T cells/ mm3 at baseline, increasing to 645 and 1395 cells/mm3 at week 12 respectively. The proportion of gut mucosal CD4 (gated on CD3+) cells increased from 40.3 to 45.8 post-IL-7 , as did the CD4 number (million cells/g tissue) from 2.5 to 4.7, most of which were memory cells.

Some inflammatory and immune activation markers in gut mucosa decreased or remained unchanged with IL-7.  Activated gut CD3+ cells increased. Although plasma sCD14  (soluble CD14 receptor, present in macrophages that combat lipopolysaccharides that permeate through the intestinal mucosa and that are caused by microbial translocation in the gut) levels did not change significantly, D-dimer levels decreased from 0.24 mg/L at BL to 0.14 mg/L at week 12 .  High levels of D-dimer have been associated with cardiovascular disease in previous studies. This study shows that IL-7 can potentially reconstitute the gut barrier after HIV infection with the possible decrease in microbial translocation.

IL-7 did not increase viral load in these patients, which has been a concern in some previous studies since IL-7 can reactivate latent HIV reservoirs.

Listing of current and closed studies with IL-7

A friendlier Tenofovir-like Drug?

GS-7340 : Tenofovir Prodrug Requires Lower Doses, But Will It Be Friendlier on Kidney and Bones?

CROI 2012- Oral Presentation  #103. GS-7340 25 mg and 40 mg Demonstrate Superior Efficacy to Tenofovir 300 mg in a 10-day Monotherapy Study of HIV-1+ Patients

GS-7340 is a novel prodrug of tenofovir (TVF) that has shown greater antiviral activity at lower doses than tenofovir disoproxil fumarate (TDF) 300 mg, achieving higher intracellular TFV-diphosphate (DP) concentration with lower systemic TFV exposure, in a prior proof-of-concept study.

This  randomized, partially blinded, placebo and active-controlled, dose-finding, 10-day monotherapy study was conducted to compare 3 different doses of GS-7340 (8, 25, and 40 mg once daily), open-label TDF (300 mg once daily), and GS-7340 placebo in HIV-1-infected subjects with HIV-1 RNA ≥2000 copies/mL, no genotypic resistance to TDF, and CD4 cell count ≥200 cells/mm3. The primary endpoint was time-weighted average HIV-1 RNA change from baseline after 10 days of treatment. Plasma and intracellular peripheral blood mononuclear cell  pharmacokinetics were also assessed.

The study found that GS-7340 at 25 mg and 40 mg demonstrated superior antiviral efficacy to TDF at 300 mg, achieving higher intracellular TFV-DP concentration with lower systemic TFV exposure. GS-7340 has the potential to be more efficacious with an improved safety margin, and to be easier to co-formulate, compared with TDF.  A later presentation also showed that this prodrug has better penetration in different body compartments compared to tenofovir.

Let’s hope that this pro drug will show less of a negative effect on kidney function and bone density than tenofovir.  Let’s also hope that its better tissue penetration is different body compartments will also result in better control of latent HIV infection in reservoirs.

Can an Alzheimer’s Drug Help HIV+ People with Cognitive Dysfunction?

CROI 2012 Paper #482.  Rivastigmine for the Treatment of HIV-associated Neurocognitive Disorders: A Randomized, Double-blind, Placebo-controlled, Crossover Pilot Study

The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite successful antiretroviral therapy.  This study performed by researchers from the HIV Swiss Cohort aimed at looking at the effect of rivastigmine on HAND in patients with undetectable HIV viral load in blood and cerebrospinal fluid but who had symptoms of neurocognitive dysfunction.

Rivastigmine (sold under the trade name Exelon) is an approved agent used in  the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson's disease.

 This was a 2-site, randomized, double-blind, placebo-controlled, crossover study in 17 HIV+ patients (12 men, mean 54.7 years old, 660  CD4+) with HAND. All patients had undetectable viremia in both plasma and cerebrospinal fluid at study entry, and no lesions on brain MRI. Participants were randomized to receive either rivastigmine by mouth (5 months) followed by identical placebo (5 months) after a 6-week wash-out period, or placebo followed by rivastigmine . Dosage was progressively increased from 1 mg to reach 12 mg per day of rivastigmine. Four study visits included neuropsychological examinations. The primary outcome was the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary endpoints were 8 cognitive measures of attention, information processing speed, working memory and executive functioning, as well as perceived quality of life (MOS-HIV). The difference between start/end values during each 5-month study period was used as a combined outcome for each subject.

Rivastigmine induced mild to moderate adverse events in 9 patients that disappeared after slight dose reduction. Four patients withdraw because of severe nausea, nightmares/anxiety, and allergic reactions. One measure of attention/processing speed improved on drug (Trail Making Test A). Executive functioning also improved but did not reach statistical significance due to the small sample size (CANTAB Spatial Working Memory). Patients showed a trend for a self-reported enhanced cognitive functioning (MOS-HIV) on drug . There was no significant improvement on the ADAS-Cog.

In small trials, drug effects need to be very large to reach statistical significance. This pilot study suggests that the use of rivastigmine in aviremic HIV+ patients with HAND may improve cognitive functions that are typically affected in HAND, i.e., information processing speed and executive functioning.

This study used an oral formulation.  It is known that a transdermal patch formulation has been better tolerated in Alzheimer’s patients, so it will be interesting to test this drug in a patch form in a larger group of patients with HAND who have undetectable viral load.

Is It Safe to Give the Shingles Vaccine to HIV Positive People?

CROI 1012: Oral presentation  #96 . ZOSTAVAX Is Generally Safe and Immunogenic in HIV+ Adults Virologically Suppressed on ART: Results of a Phase 2, Randomized, Double-blind, Placebo-controlled Trial

Risk of recurrent/severe herpes zoster (HZ) is increased in HIV+ patients.   To date, use of ZOSTAVAX® (ZV; live attenuated zoster vaccine live) has been contraindicated for people with HIV due to safety concerns, although some physicians have been prescribing it for HIV+ patients with high CD4 cells.  For those with lower CD4 cells, the standard oral herpes drugs have been commonly used for herpes outbreaks or as prophylaxis to prevent further outbreaks. This vaccine  has generally been shown to be safe and effective in reducing HZ incidence/severity in HIV negative adults ≥50 years old, but it has not been evaluated in HIV+ adults.

This ACTG study was a randomized , double-blind, placebo-controlled  to assess safety and immunogenicity of 2 doses of ZV in HIV+ adults ≥18 years old (CD4 >200 copies/µL; HIV RNA <75 copies/mL for ≥6 months on stable ART; varicella-zoster virus (VZV) seropositive, history of VZV or HZ >1 year prior to entry). Patients were stratified by screening CD4 (>350 copies/µL [High CD4] vs ≥200 to 349 copies/µL [Low CD4]), received ZV or placebo on day 0 and week 6; and were evaluated at weeks 2, 6, 8, 12, and 24.

The study enrolled 395 patients:  203 High CD4 patients (152 ZV/51 placebo) and 192 Low CD4 patients (144 ZV/48 placebo); 3 (1 ZV, 2 placebo) received no vaccine and were excluded. Patients were 84% male; 66% white, 31% black, 22% Hispanic; median age 49 years; median High CD4= 602 cells/mL, Low CD4 =283 cells/mL. Of 295 ZV patients, 15 experienced primary safety endpoints, none vaccine related. In the first 48 patients, median baseline natural log ZV antibody titer was 5.60 and was higher at week 12 for ZV  vs placebo .  Geometric mean fold-rise was 1.75 ZV vs 1.09 placebo. Week 12 VZV antibody titer (after 2 ZV doses) was similar to week 6 (1 dose). High CD4 patients had higher antibody titer than Low CD4 patients over time.

The presentation did not include data on the vaccine’s effects on patients’ HIV viral load and CD4 cells. The study team will present CD4 and HIV viral load data in the future.  Patients will not be followed beyond 24 weeks to see if the incidence of shingles does in fact decrease as much as it does in HIV negative people.

Do Friendly Bugs Improve Immune Function?

CROI 2012 Oral Presentation #95 . Probiotic Supplementation of ARV Treatment during SIV Infection of Pigtail Macaques Results in Enhanced GI Tract CD4+ T Cell Frequency and Immunological Function

During progressive HIV/SIV (simian immune defficiency virus in monkeys) infections, damage to the GI tract leads to microbial translocation, which may contribute to chronic immune activation and disease progression.

This study treated chronically SIV-infected pigtail macaques monkeys (PTM) with probiotics (brand name: Culturelle) in combination with ARV treatment, and compared to chronically SIV-infected PTM treated with ARV alone. Combination ARV therapy included 30mg/kg PMPA (a nucleoside that has been extensively used in SIV studies), 30mg/kg emtricitabine (FTC) (once daily, s.c.), and 120mg L812, 50mg L564 (twice daily, oral integrase inhibitors) for an average of 162 days.

The study team found that, compared to PTM treated with ARV alone, animals given probiotics and ARV had enhanced reconstitution of CD4+ T cells in the colon (almost double the CD4 cell counts attained by the ARV alone group) . Furthermore, probiotic treatment decreased the activation of CD4+ T cells in the colon and increased the overall functionality of colon CD4+ T cells as measured by multifunctional cytokine production, with indications of enhanced mucosal immunity.

Although this was a monkey study, the presenter hinted at the possibility of expecting similar results in humans infected with HIV.  Since probiotics do not colonize the GI track, they need to be dosed daily or frequently, however.

Undetectable HIV Viral Load in the Blood? Not Necessarily in Semen, Boston HIV Study Finds

Can someone with no detectable HIV virus in their blood due to successful HIV treatment infect someone?




"Undetectable viral loads in blood is not a guarantee that HIV is also undetectable in semen, according to a new study involving 101 HIV-positive men who have sex with men (MSM) conducted in Boston and published online ahead of print by the journal AIDS. Of the 83 men with undetectable virus in blood samples, roughly a quarter of them—21 MSM in total—had semen with detectable HIV."

"Eighty-three of the 101 MSM (men that have sex with men) had undetectable levels of HIV in their blood samples. Though most also had undetectable HIV in their semen samples, 21 (25 percent) had detectable seminal viral loads"

How long had these 21 MSM guys been on HIV meds? What was the rate of other active sexually transmitted infections in this sub group?

"..the average free-floating viral load was 4,438 copies among those with detectable blood-based HIV levels, it was 51 copies among those with undetectable blood-based HIV levels. "

Are these 51 viruses enough to infect someone?

Previous studies that looked at this found a rate of around 8 percent. And some researchers say that these viral particles may consist mostly of pro-virus and not active "infectious" virus.

I wish they had measured blood and intra-cellular levels of anti-retrovirals to see if they correlate with semen's HIV viral load.

Read this great article by Tim Horn:

http://www.aidsmeds.com/articles/hiv_semen_transmission_1667_22190.shtml

How electrical brain stimulation can change the way we think

Have you wanted to take a vacation from your own head? You could do it easily enough with liberal applications of alcohol or hallucinogens, but that's not the kind of vacation I'm talking about. What if you could take a very specific vacation only from the stuff that makes it painful to be you: the sneering inner monologue that insists you're not capable enough or smart enough or pretty enough, or whatever hideous narrative rides you. Now that would be a vacation. You'd still be you, but you'd be able to navigate the world without the emotional baggage that now drags on your every decision. Can you imagine what that would feel like?  Read more

Controversies in HIV cure research

              Great overview written in layman's terms

Controversies in HIV cure research

Journal of the International AIDS Society 2012, 15:16      doi:10.1186/1758-2652-15-1
Rowena Johnston (rowena.johnston@amfar.org) 
Francoise Barre-Sinoussi (fbarre@pasteur.fr)

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