From the book “Built to Survive (click here)
Calcium – 300 mg
or more three times per day. Take for strong bones, nerve health, and muscle
growth itself. Calcium and magnesium are nutrients that
Dr. Jon Kaiser recommends to prevent
and treat neuropathy. Optimal calcium intake improves insulin sensitivity,[i] so
calcium is another nutrient that might help reduce some lipodystrophy symptoms.
Calcium carbonate (not citrate) supplementation at 500 mg twice daily can
reduce protease inhibitor-induced
Magnesium – 200 mg
or more three times per day. Necessary for bone, heart and nerve health, and
muscle growth and strength. Also involved in healthy insulin metabolism, so
magnesium supplementation may
reduce the potential for some lipodystrophy symptoms.
Zinc – 10 to 30
mg three times per day. Improves healing and immune function. One poorly
designed questionnaire-based study suggested that having too much zinc might decrease survival in HIV.[iii] Other studies show; there is a
correlation with low zinc status and an increase in bacterial infec-tions[iv]high
dose zinc supplementation (200 mg per day) can reduce the incidence of the
deadly lung infection called pneumocystis and candida infections, and cause an increase in CD4 T cells and body weight;291
and that low zinc status in HIV is
associated with increased risk of death.24 While there is an upper
limit to how much zinc is safe (it can interfere with selenium’s
beneficial antitumor and antiviral effects), after communicating with leading
zinc researchers, I find that the potential safe upper dose limit for short
term use appears to be approximately 150 mg per day. Zinc is required for
healthy testosterone production,[v] and
IGF-1 production[vi] Zinc can inhibit the activity of several of
the herpes viruses,[vii]
and there appears to be an association between herpes and immune destruction in
HIV.283 High dose zinc has been shown to significantly
reduce cold symptoms.[viii] (To
fight herpes outbreaks and colds I take high dose zinc or use zinc acetate
lozenges myself with great success. I always add 2 mg of copper per 50 mg of zinc because copper is required
with zinc in the manufacture of a super oxide dismutase, which are important
antioxidants that are made in the body.) Zinc is best taken alone before
bedtime for optimal absorption. Nutrition
expert Dr. Richard Beach at the University of Miami says that many HIV(+)
people need 75 or more mg of zinc per day, and Dr. Baum’s study, as cited
earlier, indicated 90 mg per day was needed to get adequate blood levels for
many HIV(+) people
would not suggest overloading with zinc,
poor zinc absorption and increased need for zinc by HIV(+) people makes an
optimal level of zinc supplementation very important. (Note: an overload is not
well defined, and is very individual.) If a person is ill or is highly
progressed, it is possible that they will need as much as 90 to 200 mg of zinc
per day. High-dose zinc is generally only advisable for short periods of time,
though, and for specific reasons. Ask your doctor or a certified nutritionist
or registered dietitian if you think you might need high doses of zinc, and
show them this information because they may not be aware of it. Symptoms of
zinc deficiency are poor sense of smell and taste, slow healing, poor quality
skin and hair, and low neutrophil counts.
Selenium – 100 to
200 mcg three times per day. Works with vitamin E, and helps in the generation
of glutathione, the body’s critically important natural antioxidant. One HIV
study found correlations between CD4 T-cell counts, selenium levels, and glutathione levels.[ix] In a study of 125 HIV-infected men and
women, Dr. Marianna Baum found that patients with selenium deficiency were 19.9
times more likely to die of AIDS than patients with adequate selenium levels.[x]
She theorizes that the link between selenium and mortality is due to
selenium’s antioxidant function or action in gene regulation that might
actually affect the replication of HIV itself. “In selenium deficiency the HIV virus reproduces faster,”
Copper – 2 mg.
Necessary for healing, and helps form super oxide dismutase (SOD), an important
antioxidant enzyme in the body. If you are taking high dose zinc (more than 40 mg per day) you may need to take
more than 2 mg of copper, as high dose zinc can induce a copper deficiency. Copper
is critical to immune health and antioxidant production in the body. Ask your
doctor to test for zinc and copper deficiencies.
Chromium – 300 mcg
three times per day. Chromium supplementation improved insulin sensitivity 40
percent in a study with diabetics without toxicity at 1000 mcg per day,[xi] so
chromium is another nutrient
that might help reduce some lipodystrophy symptoms. (Chromium’s potentially
toxic dose is considered to be about 70,000 mcg per day according to the U.S.
Environmental Protection Agency.)
Iron – 18 to 50
mg. A 6-year University of California at Berkeley study showed that iron intake was highly
correlative with reducing progression of HIV to full-blown AIDS, and 54 mg
per day from food and supplements appeared to be about twice as good as 36 mg
to reduce HIV progression.308 Iron is
poorly absorbed in general, so supplementation can be very important for people
who are anemic and suffer from low energy. Iron is necessary for the production
of carnitine in the body, the
health of the red blood cells, immune health, the body’s ability to fight
bacteria, and energy production.
activity in the body is under control because there is an abundance of
antioxidants, like Vitamin E and Beta Carotene that are derived from a healthy
diet and/or dietary supplements. Optimal iron status is required for overall
health in early HIV, however, there is a potential for iron overload in HIV,
especially in the more advanced stages,[xii] or
when antioxidant status in the body is compromised, or when there is insulin resistance.[xiii] Iron
overload can increase the potential for immune problems and increased
infections, so it is advisable to ask your doctor to test and monitor body stores of iron by testing serum ferritin
in blood tests.
method of testing iron stores in the body
may not accurately reflect excess iron stored in the liver, heart, bone marrow,
etc., according to Sharon McDonnell, MD, MPH, of the Centers for Disease
Control. She says that testing for transferrin
saturation provides a more accurate indication of this kind of stored iron,
especially if it is elevated in more than one test.
those of you who do include iron in their daily
supplementation, there is one form of iron that is considered to be basically
nontoxic, even at doses in the thousands of milligrams. This form is called iron carbonyl,[xiv] and it
is the form of iron contained in the SuperNutrition and the AMNI vitamin formulas.
intraplatelet free calcium concentration and insulin resistance in essential hypertensive patients.
Hypertension (1997) 29(1 Pt 2):531-536.
nelfinavir-induced diarrhea. 39th ICAAC, Sept. 26-29,
1999 San Francisco, California. Abstract #1308.
human immunodeficiency virus type 1 infection. Am J Epidem (1996)
levels and infections in hospitalized patients with AIDS. Nutrition (1996) 12(7-8):515-518.
of dietary zinc depletion on seminal volume
and zinc loss, serum testosterone concentrations, and sperm
morphology in young men. Am J Clin Nutr (1992) Jul;56(1):148-157.
of insulin-like growth factor-1 and growth hormone in growth inhibition
induced by magnesium and zinc deficiencies. Br J Nutr (1991) Nov;66(3):505-521.
al. Zinc salts inactivate clinical isolates of herpes simplex virus in
vitro. J Clin Microbial 2000 May;38(5):1758-1762.
clinical study of the effectiveness of zinc acetate lozenges on common cold symptoms in
allergy-tested subjects. Cur Thera Res 1998, September;59:595-607.
patients with acquired immunodeficiency syndrome and AIDS-related complex. Biol
Trace Elem Res (1988) 15():167-177.
of HIV-related mortality is associated with selenium deficiency. J AIDS Hum
Retro (1997) 15:370-376.
mechanisms, possible consequences, and proposals for management. Inf Agents & Dis (1996) 5(1):36-46.
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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
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
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
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
*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
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. •
Mucosa T Lymphocyte Restoration in Chronically HIV+ Patients Treated with
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.
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.
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.
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
viral load in these patients, which has been a concern in some previous studies
since IL-7 can reactivate latent HIV reservoirs.
Friendlier on Kidney and Bones?
Superior Efficacy to Tenofovir 300 mg in a 10-day Monotherapy Study of HIV-1+
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.
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.
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
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.
HIV-associated Neurocognitive Disorders: A Randomized, Double-blind,
Placebo-controlled, Crossover Pilot Study
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
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.
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
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.
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.
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.
Immunogenic in HIV+ Adults Virologically Suppressed on ART: Results of a Phase
2, Randomized, Double-blind, Placebo-controlled Trial
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.
, 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.
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
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.