Ten News Items That Have Made Me Happy During the Past Month

These past several weeks have been great on many fronts. While taking a shower this morning, I counted a few of the great pieces of news that have come our way amidst all the negative news that the media dwells on to increase ratings. 

http://www.thebody.com/content/67329/ten-news-items-that-have-made-me-happy-during-the.html

HIV Cure Related Studies Currently Enrolling

IMMUNE BASED THERAPIES


Phase 1 Dose
Escalation Study of Autologous T-cells Genetically Modified at the CCR5 Gene by
Zinc Finger Nucleases in HIV-Infected Patients
The purpose of this research study is to find out whether
“zinc finger” modified CD4+ T-cells are safe to give to humans and
find how “zinc finger” modified T-cell affects HIV. Five
different cohorts with different patient characteristics are being recruited
Dose Escalation
Study of Cyclophosphamide in HIV-Infected Subjects on HAART Receiving Sangamo’s
SB-728-T
The purpose of the study is to evaluate the safety,
tolerability and effect on HIV viral load, of escalating doses of cyclophosphamide
administered 1 day prior to SB-728-T infusion. It is hoped that
cyclophosphamide could improve engraftment of modified T cells.
High-Dose
Chemotherapy With Transplantation of Gene-Modified 
Stem Cells for High-Risk AIDS-Related Lymphoma
Patient stem cells will be
mobilized with induction chemotherapy (R)-ICE and G-CSF. If sufficient cells can be mobilized, patients will be treated with
high-dose chemotherapy and a transplant of autologous CD34+ cells transduced with an antiviral vector (M87o). If
autologous CD34+ yield is insufficient, allogeneic gene-modified cells will be given, if a compatible donor is
available. To minimize risk of transplant failure, a second unmodified CD34+ cell transplant will be given one week after the first
transplant.

ACE Inhibitors
to Decrease Lymphoid Fibrosis in Antiretroviral-Treated, 
HIV-infected Patients:
A Pilot Study
The investigators propose a proof-of-concept,
pathogenesis-oriented, randomized, placebo-controlled pilot study to assess
whether the addition of an angiotensin converting enzyme (ACE) inhibitor to
standard Highly Active Antiretroviral Therapy (HAART) reverses lymphoid
fibrosis, and whether this leads to more effective HIV-specific host
immune responses and an accelerated clearance of the latent reservoir.
Safety and
Efficacy Study of AGS-004 During Analytical Treatment Interruption
The purpose of this study is to determine the safety and
effectiveness of AGS-004, an immune therapy, for HIV-infected
individuals. Safety and effectiveness will be tested while the individuals are
both taking antiretroviral therapy (ART) medication and interrupting ART
medication.
http://clinicaltrials.gov/ct2/show/NCT01069809?term=HIV+reservoir&recr=Open&rank=19

Allogeneic Transplant in HIV Patients (BMT CTN 0903)

The rationale for this trial is to demonstrate the feasibility and safety of allogeneic HCT for patients with chemotherapy-sensitive hematological malignancies and coincident HIV-infection. In particular, the trial will focus on the 100-day non-relapse mortality as an indicator of the safety of transplant in this patient population. Correlative assays will focus upon the incidence of infectious complications in this patient population, the evolution of HIV infection and immunological reconstitution. Where feasible (and when this can be accomplished without compromise of either the donor quality or the timeliness of transplantation), an attempt will be made to identify donors who are homozygotes for the delta32 mutation for CCR5.
http://clinicaltrials.gov/ct2/show/NCT01410344

 A randomized, double blind, phase IIB study testing the efficacy and safety of AGS-004 on host control of HIV replication during analytical treatment interruption

In this randomized, double blind, phase 2B trial, researchers will administer ASS-004 intradermally — into the skin — every four weeks at a dose of 1.2 x 10 7. In order for researchers to test AGS-004, participants will undergo a clinically controlled short-term analytical treatment interruption.
AGS-004 is created from a person’s own dendritic cells—white blood cells that stimulate the body’s immune system — and a sample of their HIV virus. This is the first experimental treatment designed from a person’s HIV genetic material and their body’s cells. Researchers believe that this study immunotherapy will boost anti-HIV immune responses in order to partially or totally control viral replication in the absence of ART or at least to significantly delay/limit the use of ART.

THERAPEUTIC HIV VACCINES


A Phase Il of a
Therapeutic, Recombinant, Biologically Active HIV-1 Tat Protein 
Vaccine in HIV-Infected, Anti-Tat Negative, ARV-Treated Adult Volunteers
(ISS T-003)
Tat is a key HIV regulatory protein produced very early after
infection, prior to virus integration, and necessary for viral gene expression,
cell-to-cell virus transmission and disease progression. Previous studies in
natural HIV infection, indicated that the presence of a Tat-specific immune
response correlates with a lower incidence and reduced risk of progression to
AIDS as compared to anti-Tat negative individuals suggesting that an immune
response to Tat may exert a protective role and control the progression to AIDS
in vivo. Moreover Tat is conserved in its immunogenic regions (both B and T
cell) among all subtypes. subtypes. Recent data, in fact, indicate an effective
cross-clade recognition of clade B strain-derived (BH-10) Tat protein from the
HTLV-IIIB lab-adapted virus strain (Buttò, 2003), which was isolated about 20
years ago (Ratner, 1985), by sera from individuals infected with viruses
circulating at the present in Italy and in Africa, thus reflecting the high
degree of conservation of the corresponding Tat regions and providing strong
formal evidence that a Tat-based vaccine may indeed
be used in the different geographic areas of the world, since it is capable of
inducing a broad immune response against different virus clades. Based on this
rationale and on the positive results of preclinical (Cafaro, Nat Med 1999) and
phase I preventive and therapeutic clinical trials with Tat protein (ISS P-001
and ISS T-001, respectively) (Ensoli AIDS 2008, Vaccine 2009; LongoVaccine 2009; Bellino RRCT, 2009) a phase II therapeutic,
open label, clinical study with Tat protein (ISS T-002, ClinicalTrials.gov
NCT00751595) was sponsored by ISS and activated in 11 clinical sites in Italy
in HIV-infected HAART-treated
subjects.In this study, subjects are randomized into two arms to receive 3 or 5
vaccinations monthly; each arm is composed of two treatment groups, receiving
7, 5 or 30 µg of Tat, respectively. Preliminary results obtained from 87
subjects enrolled in the phase II trial ISST-002 ongoing in Italy, indicate
that Tat vaccination is safe, immunogenic and capable of reducing the immune
dysregulation which persists despite HAART in treated individuals, opening new
avenues for a most effective treatment of HIV/AIDS (Ensoli et al,PLoS ONE 2010).
Immunomodulating
Therapy and Improved Vaccination Responses by Cox-2 Inhibitor in 
HIV-infected Patients (OUSCOX2)
Chronic
immune activation is a central feature of HIV-infection, and the degree of
activated T-cells is a better predictor of disease progression and mortality
than plasma viral load. The study hypothesis is that the anti-inflammatory
substance etoricoxib will dampen chronic immune activation and improve the
effect of T-cell dependent vaccines in HIV-1 infected patients.
The aim of the present study is to explore the efficacy of the
study drug on markers of immune activation and vaccine responses, as well as safety of the
study drug, in HIV-infected patients not receiving antiretroviral
therapy.
Safety and
Tolerability of a Therapeutic DNA Dendritic Cell 
Vaccine in HIV-Infected Children, Adolescents, and Young Adults
The therapeutic DNA vaccine, DermaVir, represents an immunization strategy
that targets lymph node dendritic cells. Because of the high percentage of
naive CD4 cells in children and adolescents, the potential for effective new
HIV-specific CD4 cell responses may be more achievable in children than in
adults. The primary purpose of this study is to evaluate the safety and
tolerability of DermaVir in children and young adults.
Safety and
Immune Response Assessment Study of Killed-whole HIV-1 
Vaccine (SAV001-H) in Chronic HIV-1 Infected Patients
The purpose of this study is to examine the safety,
tolerability, and immune response to killed-whole HIV-1 (SAV001-H) vaccine as a primary vaccination regimen in HIV infected individuals.
A Study to
Evaluate the Safety of the 
HIV-1 Vaccine MVA-B in
Chronic 
HIV-1 Infected
Patients Successfully Treated With HAART 
30 treated chronic HIV-1 infected patients with CD4+ cell counts above
450 cells/ mm3 will be randomized 1:2 to receive placebo (n=10) or vaccine
(n=20) at week 0, 4 and 16 and will be observed at the Investigation Unit of
the study site for one hour following vaccination. At week 24 they will stop
their HAART until the end of the study.

Redirected High Affinity Gag‐Specific Autologous T Cells for HIV Gene Therapy

This research study uses a T cell receptor (TCR) protein specific for HIV (SL9 TCR) and adds it to the CD8 T‐cells in the laboratory in order to help the CD8 T‐cells recognize the constantly changing HIV virus and make it able to fight HIV more efficiently. TCR stands for T cell receptor TCRs are found on the surface of T cells and allow the T cells to recognize other cells. Laboratory studies have shown that when CD8 T‐cells are modified with SL9 TCRs, they kill cells that are infected with HIV better than normal CD8 T‐cells can. On the basis of these laboratory results, there is the potential that SL9 TCRs may work in people infected with HIV and improve their immune system by killing HIV infected cells and thus may help control HIV infection.
Two different SL9 TCRs will be tested in this study, WT‐gag‐TCR and α/6‐gag‐TCR. Two different types of SL9 TCRs are being used in this research study because the laboratory studies suggest that the different SL9 TCRs will function differently depending on the amount of virus in your body. A goal of this clinical study is to test the effects of infusions of either SL9 TCR in the presence or absence of a viral load.
http://clinicaltrials.gov/ct2/show/NCT00991224?term=hiv-infected+vaccine&recr=Open&rank=32

Phase I/IIa Dose-escalation Clinical Study of VAC-3S

The purpose of this trial is to evaluate the safety and immunogenicity of the therapeutic vaccine candidate VAC-3S in HIV-1 infected patients under AntiRetroviral Therapy (ART) with undetectable viral loads.
http://clinicaltrials.gov/ct2/show/NCT01549119

Safety and Immunogenicity of HIVAX in HIV-1 Infected Subjects (GCHT01)

This study is to test a therapeutic HIV-1 vaccine (HIVAX™) in HIV-1 infected subjects. The safety and immune responses will be studied in vaccine recipients. The anti-viral effect of HIVAX vaccine will be monitored during a 12-week treatment interruption phase.
http://clinicaltrials.gov/ct2/show/NCT01428596

RESERVOIR RELATED

The Effect of
Vorinostat on 
HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART
The
purpose of this study is to compare HIV RNA expression within resting CD4+
cells in HIV-infected patients on stable
ART before and after a single exposure to Vorinostat (VOR).
Hypotheses: The frequency of detectable HIV RNA expression within resting CD4+ T
cells will increase after VOR exposure in vivo.
The Study of Gut
Associated Lymphocytes in 
HIV and HCV/HIV Co-infected Patients
The purpose of this research study is to explore what role
immune cells within the gut (the sigmoid colon) have locally and on the immune
system of patients infected with HCV, HIV or HCV/HIV co-infection.
Safety and
Effect on 
HIV Transcription of Vorinostat in Patients Receiving
Suppressive Combination Anti-retroviral Therapy
The objective of the study is to assess the safety and
ability of vorinostat, a drug currently licensed for the treatment of a type of
lymphoma, to ‘turn on’ dormant HIV infected
CD4 T-cells.
Tissue Drug
Levels of 
HIV Medications:
The aim of this study is to find out why HIV continues to
make copies in people taking HIV drugs. The Investigators want to know if the
medications most people use to treat HIV do not completely stop the virus from
making additional copies of HIV.
IntensVIH:
Impact Of Therapy Intensification By An Integrase Inhibitor +/- CCR5 Inhibitor
On The Lymphoid 
Reservoir For Hiv-1 
To determine
the efficacy of adding Isentress®, with or without Celsentri®, to effective
conventional antiretroviral therapy (comprising at least 2 reverse
transcriptase inhibitors and one boosted protease inhibitor), on residual HIV
replication and blood cell and gut-associated lymphoid tissue reservoirs
(reverse transcriptase inhibitors: RTIs, boosted protease inhibitors: PI/r).
To evaluate
the effect of therapy intensification by means of an integrase inhibitor with
or without CCR5 inhibitor treatment on the lymphoid reservoir in patients
chronically infected with HIV-1, successfully treated with “conventional
triple therapy”, measured by:
·       
residual
plasma replication between 0 and 50 copies/ml
·       
intracellular
HIV RNA levels in circulating lymphocytes (PBMC) and lymphocytes in
gut-associated rectal lymphoid tissue (RL).
·       
proviral
HIV DNA levels in PBMC and RL.
The Use of
Leukapheresis to Support 
HIV Pathogenesis Studies
A more complete understanding of the relationship between
inflammation and viral persistence is necessary before more rationale studies
of HIV eradication
can be designed. Also, a well validated high through-put virologic assay needs
to be developed that can estimate the size of the latent reservoir. Since the level
of replication competent virus in long-term treated patients (and in elite
controllers) is very small (< 1% of CD4 cells harbor HIV), large numbers of
CD4+
T
ce
lls most be obtained from study participants in order to
routinely isolate and quantify virus persistence.
Interferon Alpha
2b Intensification in 
HIV-Positive
Individuals on Antiretroviral Therapy
Earlier studies of HIV-infected individuals who were not on any ART
showed that interferon reduced the level of HIV in the
blood. Researchers are interested in determining whether PEGINTRON therapy will
also reduce the residual low levels of HIV in
patients who are already taking ART.
Viral Load in
Blood and Lymph Tissues of 
HIV-Infected
Individuals
Our laboratory has previously demonstrated that lymph nodes
are a major reservoir for human immunodeficiency virus (HIV) and a major site
of active virus replication in infected individuals(1-3). There is at least a
10 fold greater viral burden per given number of CD4+ T lymphocytes obtained
from the lymph nodes versus the peripheral blood in the same infected
individual. These data have been accumulated predominantly in individuals with
progressive generalized lymphadenopathy (CDC Class A1 and A2). It is unclear at
present whether this pattern holds true for all categories of HIV infected individuals. We have proposed that the
seeding of lymph nodes by HIV early in
the course of HIV infection
and the persistent production of virus in lymph nodes throughout the course of
infection are major factors in the pathogenesis of HIV in virtually all infected individuals. 
The ”
Extreme ” Cohort (CODEX)
This cohort will allow common research projects with common
fundings and a better visibility both for clinicians who see patients with
unusual phenotypes and for international research. Such a cohort will be unique
in the world by its size and the presence of these two complementary groups of
patients. The two main objectives for the ” Extreme ” cohort (CODEX)
are clinical and immunovirological. The investigators wish to precise the
impact of a prolonged untreated HIV infection,
to describe the frequency of the “immunological escapes” (CD4 T cell
decrease) or “virological escapes” (permanent or transient viral load
increase). The investigators wish to study the genetic characteristics of the
patients and those of their viruses, the innate and adaptative immune responses
directed against HIV and other
viruses, the consequences of inflammation, and the characteristics of the loss
of control.

Role of extended-released niacin on immune activation in HIV-infected patients treated with antiretroviral therapy: a proof-of-concept study

This pilot study will evaluate the effect of a drug called Niaspan®, an extended-release form of niacin (ER niacin), in individuals living with HIV who are on antiretroviral therapy (ART). Researchers will examine the ability of an oral form of ER niacin to reduce immune activation and increase CD4 cells in persons with sub-optimal immune responses despite sustained virologic suppression from ART.
Study researchers believe that by regulating an amino acid called tryptophan, niacin may decrease T cell immune activation which may enhance CD4 recovery and improve neurocognitive functions. The effect of administering ER niacin in combination with ART will be measured against a regimen of ART alone.

Impact of HIV infection and antiretroviral therapy on mucosal and systemic memory CD4 T cells

This study will assess the impact of HIV infection and antiretroviral therapy on mucosal (gut) and systemic memory CD4 T cells in treatment-naïve HIV-positive individuals within six months of infection. Researchers believe this study will generate data to better understand how HIV harms the body and how they can use this information to better design HIV therapies and vaccines in the future.

Global Health Needs Extend Beyond HIV/AIDS R&D

By Mari Serebrov
Washington Editor

A singular focus on HIV/AIDS and a lag in translating
medical discoveries into approvable medicines could be
keeping the U.S. from getting its money’s worth from R&D
aimed at addressing the most pressing global health needs.
While the U.S. government is the leading funder of R&D
for 26 of the 30 most neglected diseases and conditions
affecting the developing world, nearly 60 percent of the $1 .4
billion the U.S. invests annually in global R&D is dedicated to
HIV/AIDS research, according to a recent report from PATH’s
Global Health Technologies Coalition.
The next biggest chunk of U.S. funding, 12 percent, is
spent on tuberculosis (TB) R&D, and 10 percent goes for
malaria R&D. The rest is divided among other diseases and
conditions, such as dengue fever, that affl ict many parts of
the developing world.

http://e.thompsonmediagroupllc.com/rs/thompson/images/bwt05242012.pdf

Medical Guidelines Group in the UK says that sperm washing is no safer than effective treatment and timed intercourse

http://www.aidsmap.com/NICE-says-sperm-washing-is-no-safer-than-effective-treatment-and-timed-intercourse/page/2364056/?ic=700100

Draft UK guidance on fertility treatment says that sperm washing may no longer be necessary for couples where the man has HIV and the woman does not. As long as the man is on effective antiretroviral treatment and unprotected sex is limited to days when his partner is ovulating, “sperm washing may not further reduce the risk of infection.”

Does Testosterone Suppress the Immune System?

This question is raised out of the confusion over the use of the term “steroid.”  When somebody is having pain or inflammation and their physician prescribes them a “steroid” or something “steroidal”, they are prescribing a corticosteroid (like prednisone) to decrease inflammation. These can have an immunosuppressive effect (sometimes it is intended to decrease inflammation).  The “steroid” that you hear about from the media when they are talking about use and abuse by athletes refers to an anabolic steroid (like testosterone). The similarities largely end with their street names.
Some in vitro and animal data do suggest that high dose testosterone could be immune suppressive. No such immunosuppressive effect is seen when testosterone was added at replacement concentrations.  Several studies using testosterone alone or on combination with oxandrolone or nandrolone in HIV-positive immune compromised patients have found no immune suppressive effect. Testosterone has been used in HIV since 1992 without any reports of immune related problems.
PERSONAL COMMENT: I have lived with immune dysfunction for 27 years and testosterone has not worsened it. In fact, it may have helped me retain the mood, appetite, and muscle mass needed for good immune function.

FDA Advisors Endorse Truvada to Prevent HIV Infection–But Big Questions Remain



Mark Mascolini (natap.org)

An FDA advisory panel left little doubt that Truvada, the once-daily pill combining tenofovir and emtricitabine, will get its license extended to cover pre-exposure prophylaxis (PrEP) of HIV infection in adults with a high risk of picking up HIV sexually. But the thorny deliberations leading to that endorsement in a marathon 12.5-hour session posed several tough questions about how Truvada PrEP will work in practice:

— Will people take Truvada consistently enough to protect themselves from HIV?

— If they take Truvada haphazardly and get infected, will resistance mutations evolve quickly?

— Will providers religiously test people for HIV before prescribing PrEP, and how often should they retest?

— Will Truvada PrEP work in women as well as men?

— Will taking PrEP make people abandon condoms and other HIV-evading tactics?

— How often must PrEP takers be monitored for kidney and bone problems?

— Will the side effects seen with Truvada prove too high a price for healthy HIV-negative people?

The FDA’s Antiviral Drugs Advisory Committee wagered that the answer to the last question will be no, at least not for sexually active people with risky liaisons. Panelists voted 19 to 3 to recommend Truvada PrEP for HIV-negative men who have sex with men (MSM) and 19 to 2 (with 1 abstention) for HIV-negative people with a positive partner (HIV-discordant couples). The vote favoring PrEP for “other individuals at risk for acquiring HIV through sexual activity” was 12 to 8 with 2 abstentions.

The tepid endorsement of PrEP for “other individuals” reflected committee discomfort with a relative lack of evidence that daily Truvada wards off HIV in people not studied in the two big placebo-controlled trials Gilead Sciences relied on to buttress its PrEP application: iPrEx enrolled 2499 MSM in South and North America, South Africa, and Thailand [1], and Partners PrEP signed up 4747 HIV-discordant couples in Kenya and Uganda [2]. A smaller trial, TDF2, assessed daily Truvada PrEP in heterosexual Batswana women and men not necessarily in partnerships [3].

HIV risk reduction with Truvada in primary analyses of those three placebo-controlled trials stood at 44% in iPrEx, 75% in Partners PrEP, and 62% in TDF2. In Partners PrEP tenofovir alone cut HIV acquisition risk 67%. But Truvada did not protect high-risk African women from HIV in the FEM-PrEP trial, largely because of poor adherence to the daily regimen in these 2120 women [4]. The VOICE trial in 5029 African women closed its tenofovir-only arm when early results showed this strategy wasn’t working [5]. VOICE also shut down its 1% tenofovir vaginal gel arm, but a blinded comparison of Truvada and placebo continues.

PrEP has not been tested in US women or heterosexual men, so no one can say certainly how well Truvada PrEP will work for them or whether they will even consider taking a sometimes-toxic pill every day to shield themselves from HIV. But there seems little doubt that we’ll find out. Although an advisory committee recommendation does not oblige the FDA to follow suit, the FDA probably will: Scrutinizing PrEP trial data, FDA analysts determined that those findings support the “safety and efficacy of [Truvada] for the prevention of HIV-1 infection in high-risk individuals.”

The FDA presentation leading to that conclusion did dwell deliberately on toxicity data, and the agency underlined the risk of kidney trouble in its premeeting briefing conclusion: “The decision to prescribe [Truvada] for the prevention of sexual acquisition of HIV infection should carefully weigh the individual risks for acquiring HIV, their understanding of the importance of adherence to medication, and their potential for development of renal toxicity” [6].

Can PrEPers withstand the side effects?
Not hurting people more than you help them is a hallowed tenet of medical practice, cited more than once at the FDA PrEP hearing. Clinicians rarely prescribe medicines for otherwise healthy people. Probably the most notable exception relevant to HIV care is prescription of hormonal contraceptives to women living in areas with high HIV prevalence because the family-planning benefit seems to outweigh a possibly heightened risk of HIV infection, the World Health Organization says [7].

Emtricitabine is among the least toxic drugs on pharmacy shelves, but tenofovir carries two much-studied risks–kidney trouble and bone density loss. Partly because of these threats, Gilead scientists are racing to develop a potentially gentler tenofovir prodrug, labeled GS-7340, to replace tenofovir in QUAD, the 4-in-1 tablet also containing emtricitabine, elvitegravir, and cobicistat [8-10], and possible in a 2-in-1 tablet with emtricitabine. But tenofovir-containing Truvada is the PrEP pill people will have to take for now.

In the successful PrEP trials completed so far–iPrEx [1], Partners PrEP [2], and TDF2 [3]–people took Truvada for an average of about 2 years, so you can’t judge the long-term side effect potential. But you can reckon the 2-year risk in PrEP takers, and you can gauge longer-term risks in HIV-positive people taking tenofovir alone, in Truvada, or in Atripla. (from Jules: see my report on 2nd generation PrEP where there are numerous additional PrEP therapies in research now, of course the efficacy & safety may or may not be better than Truvada or GS-7340. Although intermittent Truvada is an alternate being researched, discussed in my 2nd Generation PrEP Report, and may have less safety concerns regarding renal/bone side effects, but this remains to be seen & intermittent Truvada means timing it before & after sex so there are inherent risks of poor timing.)

Hardly any men in iPrEx had gastrointestinal trouble after starting Truvada, and rates of diarrhea, nausea, vomiting, and all GI disorders were similar in the Truvada and placebo groups. Men randomized to Truvada did endure abdominal pain more often than placebo takers (4% versus 2%, P = 0.01), and they lost weight slightly more often than the placebo group (3% versus 2%, P = 0.04). But all side effect rates in iPrEx must be judged in light of the poor overall adherence in that trial (see “Will people without HIV take Truvada regularly?” below). In the TDF2 study of heterosexual men and women in Botswana [3], nausea, vomiting, and dizziness affected significantly more people randomized to Truvada than placebo [6].

In its review at the PrEP hearing, the FDA noted that 7 iPrEx men interrupted Truvada because of climbing creatinine, compared with 3 men assigned to placebo. Six of these 7 Truvada takers restarted Truvada “without further incident.” Four Partners PrEP participants stopped tenofovir or Truvada because creatinine clearance fell to or below 50 mL/min, while 1 stopped placebo for that reason. Creatinine clearance climbed back above 50 mL/min after tenofovir stopped. In both trials, the FDA said, creatinine changes were not linked to clinical problems or other lab abnormalities.

Hypophosphatemia was the leading moderate to severe adverse event related to study drugs in Partners PrEP, affecting 11% assigned to tenofovir alone, 14% assigned to Truvada, and 13% assigned to placebo [6]. Only 6% in any study arm had serum phosphorus levels below 2 mg/dL at any point during follow-up. Neutropenia affected slightly more people taking Truvada (18%) than tenofovir alone (15%) or placebo (13%).

Seven people permanently stopped their study drug in Partners PrEP, 6 because of grade 2 renal toxicity: 3 people taking tenofovir, 2 taking Truvada, and 1 taking placebo [6]. Five of these 6 toxicities occurred in women, and all 5 had normal estimated creatinine clearance. Treatment-emergent creatinine elevations were recorded in 5% randomized to tenofovir, 7% randomized to Truvada, and 5% randomized to placebo. Only 0.2% of Partners PrEP participants had creatinine elevations judged to be drug-related, 3 people taking tenofovir alone and 5 taking placebo.

In an iPrEx bone mineral density (BMD) substudy, average BMD rose in the placebo group during the trial, while the Truvada group had small but significantly greater losses in hip and spine BMD compared with placebo takers [6]. DEXA scans done after Truvada stopped showed BMD values inching back toward baseline levels.

In a DEXA-based BMD analysis of the CDC 4323 PrEP study in 210 MSM [11,12], 10% of study participants had low BMD (a Z score at or below -2.0) when they entered the trial [12]. Median age in these men was 41. About 70% were white and 5% black. Men who used amphetamines had almost a 6 times higher risk of low BMD, and men who used inhalants had more than a 4 times higher risk. Men taking multivitamins, calcium, or vitamin D had about a 75% lower risk of low BMD.

Over time, men randomized to tenofovir had an average 1.1% drop in BMD at the femoral neck compared with the placebo group, an average 0.8% drop at the total hip, and an average 0.7% drop at the lumbar spine. After 24 months, 13% of men randomized to tenofovir and 6% randomized to placebo had more than 5% BMD loss at the femoral neck, but that difference stopped short of statistical significance (P = 0.13).

In the TDF2 PrEP trial of men and women in Botswana, people randomized to Truvada had small but significantly greater BMD declines in the forearm, hip, and lumbar spine than did with people assigned to placebo [6]. DEXA scanning was not part of the Partners PrEP protocol.

Long-time tenofovir toxicity findings in HIV-positive populations may not apply directly to HIV-negative PrEP users because the virus itself could affect kidney function and bone density, because HIV-positive people may have other conditions that affect kidneys and bones, and because people with HIV are taking other possibly toxic antiretrovirals. But results of several studies provide some perspective on what long-term tenofovir can do, and often statistical analyses in these studies considered the impact of other kidney and bone risk factors.

One long-term tenofovir study involved 10,841 HIV-positive US veterans, 98% of them men [13]. While 4303 (40%) had taken tenofovir, 6538 had not. Median age in this national sample was 45 years (interquartile range [IQR] 39 to 52) in the tenofovir group and 47 (IQR 40 to 52) in the no-tenofovir group. About half in both groups (47% tenofovir, 51% no tenofovir) were black, while 46% and 39% were white. In the tenofovir group, 38% had hypertension, 7% diabetes, 15% abnormal lipids, and 14% hepatitis C virus infection. Only 18% smoked. Proportions were similar in the no-tenofovir group.

The researchers evaluated potential associations between tenofovir use and time to first occurrence of three kidney-related endpoints: (1) proteinuria (two consecutive urine dipstick measurements ≥ 30  mg/dL), (2) rapid decline in kidney function (≥ 3 mL/min per 1.73 m annual decline), and (3) chronic kidney disease (CKD, estimated glomerular filtration rate < 60 mL/min per 1.73  m).

Median follow-up ranged from 3.9 years for proteinuria to 5.5 years for CKD. Maximum follow-up reached 11 years. Multivariate analysis that factored in demographics, HIV-related factors, other morbidities, and other antiretrovirals determined that each year of tenofovir use independently raised the risk of all three endpoints:

Increase in risk of new renal endpoint with each year of tenofovir therapy [13]:
— 34% for proteinuria (95% confidence interval [CI] 25 to 45, P  <  0.0001)
— 11% for rapid decline in kidney function (95% CI 3 to 18, P  =  0.0033)
— 33% for CKD (95% CI 18 to 51, P  <  0.0001)

Having kidney disease risk factors, CKD, diabetes, or hypertension before starting tenofovir did not seem to worsen tenofovir’s impact on the kidney. Among people who stopped tenofovir, risk of these kidney changes did not appear to drop during follow-up (see note 14). These researchers believe their findings “provide strong evidence that tenofovir may cause clinically significant toxicity to the kidney that is not reversible.” They note that “the balance between [tenofovir] efficacy and probable adverse effects requires further study.” That is all the more true for people taking tenofovir to prevent HIV rather than to treat it.

A systematic review of 17 prospective studies (including 9 randomized trials) comparing tenofovir-containing treatment regimens with nontenofovir regimens documented a significantly greater loss of kidney function in the tenofovir group (mean difference in calculated creatinine clearance 3.92 mL/min, 95% CI 2.13 to 5.70) and a greater risk of acute renal failure (risk difference 0.7%, 95% CI 0.2 to 1.2) [15]. This analysis yielded no evidence that tenofovir heightened risk of severe proteinuria or hypophosphatemia.

“Although [tenofovir] use was associated with a statistically significant loss of renal function,” these investigators concluded, “the clinical magnitude of this effect was modest” [15]. They do not believe these findings suggest a need to restrict tenofovir use in places “where regular monitoring of renal function and serum phosphate levels is impractical.”

Another Veterans Affairs study, this one involving 56,660 HIV-positive people seen from 1998 through 2009, found that every year of tenofovir therapy upped the risk of osteoporotic fracture about 12% in the combination antiretroviral era [16]. Of these 56,660 people (98% of them men), 39,277 (69%) took antiretrovirals for at least 1 month. The researchers defined osteoporotic fracture as fracture of the wrist, vertebrae, or hip. They weighed potential osteoporotic risk factors in two multivariate models, the first controlling for race, age, tobacco use, diabetes, body mass index, and hepatitis C status, the second controlling for all those factors plus concomitant antiretroviral exposure. Neither model factored in other possibly telling variables, such as glucocorticoid use or vitamin D deficiency. The study did not evaluate BMD and could not verify the fractures as osteoporotic.

Multivariate analysis determined that each year of tenofovir therapy raised the risk of osteoporotic fracture 6% (hazard ratio [HR] 1.06), but the 95% confidence intervals with model 1 and model 2 both just crossed 1.00 (0.99 to 1.12 and 0.99 to 1.14). Among 33,439 people who entered the cohort in the combination antiretroviral era, each year of tenofovir therapy independently inflated fracture risk 12% to 13% (model 1 HR 1.13, 95% CI 1.05 to 1.21, P= 0.001; model 2 HR 1.12, 95% CI 1.03 to 1.21, P = 0.011). Taking tenofovir with a protease inhibitor made osteoporotic fracture even more likely (HR 1.16, 95% CI 1.04 to 1.30). White race, older age, tobacco use, body mass index below 20 kg/m2, and HCV coinfection also heightened fracture risk; but cumulative antiretroviral use, chronic kidney disease, and diabetes did not.

AIDS Clinical Trials Group (ACTG) study A5224s sized up DEXA-measured changes in spine and hip BMD in 269 antiretroviral-naive people randomized to tenofovir/emtricitabine versus abacavir/lamivudine plus efavirenz or atazanavir/ritonavir through 96 weeks of treatment [17]. Most participants (85%) were men, and median age was 38 years; 47% were white, 33% black, and 16% Hispanic. One third (32%) had broken a bone before signing up for the study.

At week 96 mean percent decline in spine BMD was greater with tenofovir/emtricitabine than with abacavir lamivudine (-3.3% versus -1.3%, P = 0.004), as was hip BMD decline (-4.0% versus -2.6%, P = 0.024). A 96-week regression analysis that accounted for gender, age, race/ethnicity, and pretreatment viral load, CD4 count, and body mass index found significant associations between abacavir/lamivudine versus tenofovir/emtricitabine and greater BMD at the spine and hip. Abacavir/lamivudine plus efavirenz was the only combination not associated with a significant 96-week drop in spine bone density. One in 20 people (5.6%) had trauma-related fracture during the study, but the fracture rate and time to first fracture did not differ by treatment assignment during these 96 weeks of observation.

A Spanish longitudinal study of 671 antiretroviral-treated people found higher odds of BMD loss or progression to osteopenia/osteoporosis with longer time taking tenofovir (odds ratio [OR] 1.08, 95% CI 1.03 to 1.14, P < 0.0019), longer time taking a protease inhibitor (OR 1.18, 95% CI 1.12 to 1.24, < 0.0001)), and current protease inhibitor use (OR 1.64, 95% CI 1.35 to 2.04, P < 0.0001) [18]. Most cohort members (72%) were men, median age was 42.1, median time on antiretroviral therapy was 7.4 years, median time on tenofovir was 2.2 years, and 52.5% were taking tenofovir at the time of evaluation. Through 2.5 years of follow-up, 12.5% of study participants had a new diagnosis of osteopenia and 15.6% a new diagnosis of osteoporosis.

Together these PrEP trials and antiretroviral therapy studies confirm that taking tenofovir for even a few years poses threats to kidneys and bones. In licensing tenofovir and Truvada for antiretroviral therapy, the FDA judged that the benefits of tenofovir-containing regimens outweigh these risks at the population level. In voting to recommend Truvada as PrEP for HIV-negative people, the Antiviral Drugs Advisory Committee figured that the preventive benefit of this 2-in-1 pill outweighs these risks on the population level. But the individual risk/benefit equation clearly varies from person to person.

For example, black men in the United States run a higher risk of chronic kidney disease than white men. At the same time, black MSM account for a disproportionate fraction of new HIV infections in the United States [19]. As a result, they are prime candidates for Truvada PrEP. How aggressively clinicians evaluate kidney function in HIV-negative men before prescribing Truvada–and how closely they follow kidney function after PrEP begins–remain pressing questions, especially in blacks. (Notably, fewer than 10% of iPrEx MSM were black and only 10% lived in the United States.) On the other hand, white men in the United States run a higher risk of BMD loss than black men. So clinicians will have to ask the same questions about evaluating and monitoring bone loss in white MSM eager to try Truvada PrEP.Will people without HIV take Truvada regularly?Whether people will take Truvada PrEP consistently enough to ward off HIV is anyone’s guess. Some undoubtedly will take the pill daily or almost daily–as long as it causes no side effects that they feel or that monitoring detects. But others may ignore instructions and decide to take the pill only when they expect to have sex, or they may remember to take it only after sex, turning the strategy into postexposure prophylaxis. Irregular Truvada taking may yield blood and cell drug levels too low to shut out HIV. Truvada PrEP trials and other findings offer some insight into possible Truvada adherence outside the clinical trial arena.

In iPrEx pill-dispensation rates indicated that Truvada use dropped from 99% to 91% during the first year of the study [1]. But adherence looked much worse when the investigators measured levels of tenofovir diphosphate–the drug’s active form–in blood cells. This analysis showed better adherence in men who reported unprotected receptive anal intercourse, men over 25 years old, and men with at least a secondary education. But in all these analyses, fewer than half of the men tested had detectable tenofovir diphosphate in blood cells [6]:

Proportions of iPrEx men with tenofovir diphosphate detectable in blood cells:
— Reported unprotected receptive anal intercourse: 44 of 103 (43%)
— Reported no unprotected receptive anal intercourse: 7 of 30 (23%)
— 25 or older: 31 of 68 (46%)
— Younger than 25: 20 of 65 (31%)
— At least secondary education: 43 of 103 (42%)
— Less than secondary education: 8 of 30 (27%)
— Remained HIV-negative: 51 of 133 (38%)
— Became infected with HIV: 4 of 48 (8%)

It’s important to remember, though, that only 10% of iPrEx enrollees lived in the United States, in San Francisco or Boston. When iPrEx investigators measured tenofovir diphosphate levels in blood cells, they detected tenofovir in 94% of US men versus 43% of non-US men, a highly significant difference (P < 0.001).An FDA analysis presented at the PrEP hearing indicated that iPrEx men with measurable intracellular drug concentrations had an 87.5% lower risk of HIV infection (95% confidence interval 66% to 95%) than men taking placebo.

African women with a high HIV risk had poor adherence in FEM-PrEP [4]. Fewer than 26% had consistently detectable tenofovir levels in plasma, and the trial stopped because researchers determined adherence was too low to assess efficacy. In contrast, pill counts indicated that 97% of Partners PrEP women and men (HIV-negative people with positive partners) adhered to daily Truvada [2]. Analysis of tenofovir plasma levels in a subset of Partners PrEP participants determined that tenofovir was always measurable in 63% of people who remained HIV-negative and sometimes measurable in 28% who remained negative. But tenofovir could always be measured in plasma among only 15% who became infected during the trial and could sometimes be measured in 46%.

Taken together, these findings suggest that HIV-negative people who know their partner has HIV (like Partners PrEP participants) will adhere to Truvada PrEP better than HIV-negative people who don’t know their partners’ HIV status (like iPrEx and FEM-PrEP participants). And adherence rates may well be lower in clinical practice, because follow-up will be less stringent than in trials and because clinicians will have less time to preach adherence than trial staffers do.

Researchers in these PrEP trials instructed participants to take Truvada daily, but modeling work by iPrEx investigators suggests less frequent dosing may yield drug concentrations high enough to block HIV [20]. This analysis figured that taking 7 Truvada doses weekly pumped intracellular concentrations high enough to lower HIV risk 99% compared with placebo (95% CI 96% to >99%), while taking only 4 doses per week cut the risk by 96% (95% CI 90% to >99%). But intracellular concentrations attained with twice-weekly dosing trimmed the HIV risk by only 76% (95% CI 56% to 96%).

Reviewing these findings at the FDA hearing, iPrEx principal investigator Robert Grant (University of California, San Francisco) stressed that daily dosing should still be recommended with Truvada PrEP because that’s the only dose schedule tested in trials and because it’s easier to follow than 4-times-weekly dosing. But he suggested that once-daily dosing does provide some forgiveness if adherence falls short of 100%: “If they miss a few [doses per week], there will be some protection,” he proposed. At the hearing the FDA stressed that regular adherence counseling will be essential with PrEP.

Does PrEP work in women as well as men?
Truvada’s failure to protect high-risk African women from HIV in FEM-PrEP [4], its success among MSM in iPrEx [1], and the higher infection rate in women than men in Partners PrEP [2] left some with the impression that the strategy works better in men than women. But gender-based analyses of Partners PrEP [2] and TDF2 [3] disclose no significant difference in Truvada PrEP efficacy between women and men.

TDF2, the smaller of those two studies, randomized 1219 heterosexual adults in Botswana, 557 of them (46%) women, and the trial was not powered to support conclusions based on gender [3]. But comparisons of HIV seroconverters in the Truvada arm versus the placebo arm suggest that Truvada protected both women and men from HIV. In the primary analysis involving 33 seroconverters, Truvada lowered HIV risk 80.1% among men (95% CI 24.6% to 96.9%, P = 0.026) and 49.4% in women (95% CI -21.7% to 80.8%, P = 0.107). Limiting the analysis to 23 people who seroconverted during the trial, the investigators calculated 75.5% protective efficacy in women (95% CI 23.8% to 94.4%, P = 0.021) and 82.4% efficacy in men (95% CI -2.8% to 99.1%, P = 0.065).

Results are more clearcut in the larger Partners PrEP trial, which randomized 4747 HIV-discordant couples to tenofovir alone, Truvada, or placebo; approximately one third of HIV-negative partners in these couples were women [2]. During the trial, 45 women became infected, 8 in the tenofovir-only arm, 9 in the Truvada arm, and 28 in the placebo arm. Among the 37 men who became infected during the study, 9 were taking tenofovir alone, 4 were taking Truvada, and 24 were taking placebo. The higher infection incidence in women, who made up a lower proportion of HIV-negative partners, probably reflects the higher susceptibility of women than men to HIV during vaginal sex.

Among people randomized to tenofovir alone, protective efficacy was 71% in women (95% CI 37% to 87%, P = 0.002) and 63% in men (95% CI 20% to 83%, P = 0.01), and the difference between genders was not significant (P = 0.65). Among people assigned to Truvada, protective efficacy was 66% among women (95% CI 28% to 84%, P = 0.005) and 84% among men (95% CI 54% to 94%,P < 0.001). And again the between-gender difference was not significant (P = 0.24).

Chances of resistance and risk compensation seem lowTwo other concerns about Truvada PrEP in practice are resistance and so-called risk compensation–the possibility that people taking Truvada PrEP will feel invulnerable to HIV and stop using condoms or taking other measures to avert infection. Neither threat became reality in the main trials dissected at the FDA hearing, iPrEx [1], Partners PrEP [2], TDF2 [3], and FEM-PrEP [4].

Resistance mutations could be detected in trial participants assigned to Truvada, but in every case analyzed, those people appeared to have undetected HIV infection when the trial began or to become infected with resistant virus. Of course the same thing could happen when PrEP is deployed in the community if providers do not rigorously test people for HIV right before prescribing Truvada PrEP, if people have early infection that does not register on standard antibody testing when they start PrEP, or if people get infected after their last negative HIV test and then start PrEP.

Once an HIV-negative person starts Truvada PrEP, though, emergence of resistant virus seems unlikely. Based on resistance data gathered so far, Robert Grant proposed that tenofovir and emtricitabine concentrations high enough to select resistant virus should also be high enough to prevent infection. And Grant is no novitiate when it comes to HIV resistance: much of his pre-iPrEx research focused on HIV resistance.

Another resistance expert who spoke at the FDA hearing, John Mellors (University of Pittsburgh), put it this way: no or low drug exposure with PrEP will allow infection but will not select resistant virus, while good drug exposure will block infection and so obviate any risk of resistance. But Mellors did leave the resistance-risk window open a crack, saying “resistance is still possible at drug exposures that permit infection but also provide selection of resistant virus,” though he added that this possibility “appears to be uncommon.”iPrEx and Partners PrEP produced no evidence of risk compensation when people started taking pills. In fact, results indicate that people practiced safer sex once the trials began–perhaps because of regular on-study counseling and because taking antiretrovirals every day reminded them of HIV risk. In iPrEx 60% of MSM reported unprotected receptive anal intercourse when the trial began, Grant reported at the hearing. That rate fell to about 30% at study week 12 and stayed there through 144 weeks of follow-up. Baseline prevalence of any sexually transmitted infection (STI) stood at 16% in both the Truvada arm and the placebo arm. During iPrEx, STI incidence was 12.6 per 100 person-years among those assigned to Truvada and 12.2 per 100 person-years in the placebo group.

Partners PrEP investigator Jared Beaten (University of Washington, Seattle) reported that 27% of couples in that trial said they had unprotected sex in the past month when they enrolled. That proportion fell steadily throughout the trial to about 10% at month 30.

At the hearing the FDA concluded that “risk compensation was not observed” in iPrEx or Partners PrEP and that “resistance was identified only in individuals who took tenofovir or tenofovir/emtricitabine during early infection, prior to diagnosis.”

The drug-level/resistance dynamics observed in these trials will probably apply to routine Truvada PrEP use. But it’s easy to imagine that risk compensation will differ with sexually active adults who make clinic visits and get reinforcement less often than trial participants, as discussed in the next section.

“Risk mitigation,” HIV testing, and safety monitoring
To help PrEP users hew to safer sex practices, Gilead devised a risk evaluation and mitigation strategy (REMS) that provides “comprehensive education and information materials emphasizing the importance of (1) a comprehensive HIV prevention strategy, (2) regular HIV testing (before initiation and regularly while on PrEP), and (3) provider assessment for acute HIV infection prior to starting and continuing PrEP.” The REMS package Gilead promised will include:

— A notification letter to healthcare providers on details of PrEP
— Full prescribing information
— Medication guide with every bottle of Truvada
— Training guide for healthcare professionals
— Prescriber safety brochure
— Individual safety brochure
— Truvada wallet card

Advisory Committee chair Judith Feinberg (University of Cincinnati) argued that Gilead’s REMS is “utterly passive” and does not jibe with a point the FDA underlined in defining the elements of REMS: “Drug will be dispensed to patients with evidence of safe-use conditions.” Feinberg and other committee members urged Gilead and the FDA to hammer out a tougher plan that encourages prescribers to test PrEP users regularly for HIV–and possibly HBV–and to watch for side effects, while coaxing PrEP users to keep wearing condoms. In response the FDA affirmed that the agency and Gilead must agree on REMS before the agency takes regulatory action.
At the same time Advisory Committee members and FDA officials agreed that requirements for HIV testing and safety monitoring cannot be so burdensome that they discourage high-risk people from trying PrEP or sticking with it. Finding a balance between a REMS that is not too wimpy yet not too wearisome will require Solomonic sagacity. The CDC has already taken a stab at striking that balance in its interim guidance for PrEP in MSM, outlined at the end of this article [21].

Besides REMS and heightened pharmacovigilance for Truvada PrEP, Gilead promised an array of benefits for providers and PrEPers:

— Free HIV and HBV testing
— Free condoms
— Subsidized HIV-1 resistance testing for people who get infected
— An opt-in reminder service for HIV and STI testing
— Voluntary participation in a PrEP registry for prescribers and users
— Support for community education activities
— Truvada PrEP assistance program for people without prescription coverage

The last item may assume greater or lesser importance depending on whether insurers cover Truvada PrEP. The annual tab for daily Truvada as treatment exceeds $10,000. And some panelists wondered whether the PrEP registry should be voluntary or mandatory. One member observed that rates of miscarriage and birth defects with isotretinoin (Accutane) remained unacceptably high until creation of the mandatory iPLEDGE registry for women, men, prescribers, and pharmacies [22].

In its briefing document for the PrEP hearing [6], the FDA set out some guidelines for Truvada PrEP prescribing, HIV testing, and follow-up:– “The decision to prescribe [Truvada] for the prevention of sexual acquisition of HIV infection should carefully weigh the individual risks for acquiring HIV, their understanding of the importance of adherence to medication, and their potential for development of renal toxicity.

— “Education about PrEP and behavioral counseling are critically important.

— “Baseline evaluation of individuals should include HIV testing, assessment of renal function, serum phosphorous, and assessment for the presence of risk factors for development of renal or bone toxicities.

— “Consideration should also be given to providing the individual with vitamin D and calcium supplementation.

— “Periodic evaluation of the individual during PrEP administration should include regular HIV testing and monitoring for the development of renal dysfunction.

— “DEXA scans prior to and periodically during treatment may be considered for some individuals.”When iPrEx investigators first detailed their findings in 2010 [1], the CDC promptly issued “interim guidance” for Truvada PrEP in MSM [22]. Fundamentals of that advice will probably carry over to provider and user guidelines formulated by the FDA. The CDC calls for HIV and HBV testing before starting PrEP, daily Truvada dosing, prescriptions with no more than a 90-day supply, repeat HIV testing every 2 to 3 months, and regular adherence counseling and STI testing. But those guidelines, which follow here, say nothing about side-effect monitoring:

CDC interim guidance for health-care providers electing to provide preexposure prophylaxis (PrEP) for the prevention of HIV infection in adult men who have sex with men and who are at high risk for sexual acquisition of HIV [1]

Before initiating PrEP
Determine eligibility— Document negative HIV antibody test(s) immediately before starting PrEP medication.– Test for acute HIV infection if patient has symptoms consistent with acute HIV infection. — Confirm that patient is at substantial, ongoing, high risk for acquiring HIV infection.– Confirm that calculated creatinine clearance is ≥60 mL per minute (via Cockcroft-Gault formula).

Other recommended actions — Screen for hepatitis B infection; vaccinate against hepatitis B if susceptible, or treat if active infection exists, regardless of decision about prescribing PrEP. — Screen and treat as needed for STIs.

Beginning PrEP medication regimen— Prescribe 1 tablet of Truvada (TDF [300 mg] plus FTC [200 mg]) daily.– In general, prescribe no more than a 90-day supply, renewable only after HIV testing confirms that patient remains HIV-uninfected.– If active hepatitis B infection is diagnosed, consider using TDF/FTC for both treatment of active hepatitis B infection and HIV prevention. — Provide risk-reduction and PrEP medication adherence counseling and condoms.

Follow-up while PrEP medication is being taken— Every 2-3 months, perform an HIV antibody test; document negative result. — Evaluate and support PrEP medication adherence at each follow-up visit, more often if inconsistent adherence is identified.– Every 2-3 months, assess risk behaviors and provide risk-reduction counseling and condoms. Assess STI symptoms and, if present, test and treat for STI as needed.– Every 6 months, test for STI even if patient is asymptomatic, and treat as needed.– 3 months after initiation, then yearly while on PrEP medication, check blood urea nitrogen and serum creatinine.

On discontinuing PrEP (at patient request, for safety concerns, or if HIV infection is acquired)— Perform HIV test(s) to confirm whether HIV infection has occurred. — If HIV positive, order and document results of resistance testing and establish linkage to HIV care.– If HIV negative, establish linkage to risk-reduction support services as indicated.– If active hepatitis B is diagnosed at initiation of PrEP, consider appropriate medication for continued treatment of hepatitis B.

 Related papers:


References
1. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587-2599. http://www.nejm.org/doi/full/10.1056/NEJMoa1011205.
2. Baeten J, Donnell D, Ndase P, et al. ARV PrEP for HIV-1 prevention among heterosexual men and women. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 29.http://www.natap.org/2012/CROI/croi_57.htm.
3. Thigpen MC, Kebaabetswe PM, Smith DK, et al. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011 Rome. Abstract WELBC01.
4. Van Damme L, Corneli A, Ahmed K, et al. The FEM-PrEP trial of emtricitabine/tenofovir disoproxil fumarate (Truvada) among African women. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 32LB. http://www.natap.org/2012/CROI/croi_19.htm.
5. National Institute of Allergy and Infectious Diseases. NIH modifies ‘VOICE’ HIV prevention study in women: oral tenofovir discontinued in clinical trial. September 29, 2011.http://www.niaid.nih.gov/news/newsreleases/2011/Pages/VOICEmodified.aspx.
6. FDA Review Team for NDA 21-752/S-30. Background Package for NDA 21-752/Supplement 30. April 16, 2012.http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM303213.pdf.
7. World Health Organization. Hormonal contraception and HIV: technical statement. February 16, 2012. http://whqlibdoc.who.int/hq/2012/WHO_RHR_12.08_eng.pdf.
8. Ruane P, DeJesus E, D Berger D, et al. GS-7340 25 mg and 40 mg demonstrate superior efficacy to tenofovir disoproxil fumarate 300 mg in a 10-day monotherapy study of HIV-1+ patients. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 103. http://www.natap.org/2012/CROI/croi_29.htm.
9. Markowitz M, Zolopa A, Ruane P, et al. GS-7340 demonstrates greater declines in HIV-1 RNA than TDF during 14 days of monotherapy in HIV-1-infected subjects. 18th Conference on Retroviruses and Opportunistic Infections. February 27 to March 2, 2011. Boston. Abstract 152LB.
10. Ramanathan S, Wei X, Custodio J, et al. Pharmacokinetics of a novel EVG/COBI/FTC/GS-7340 single tablet regimen. 13th International Workshop on Clinical Pharmacology of HIV Therapy. April 16-18, 2012. Barcelona. Abstract O_13. http://www.natap.org/2012/pharm/Pharm_13.htm.
11. Grohskopf L, Gvetadze R, Pathak S, et al. Preliminary analysis of biomedical data from the phase II clinical safety trial of tenofovir disoproxil fumarate (TDF) for HIV-1 pre-exposure prophylaxis (PrEP) among U.S. men who have sex with men (MSM). 18th International AIDS Conference. July 18-23, 2010. Vienna. Abstract FRLBC102. http://www.iasociety.org/Default.aspx?pageId=11&abstractId=200741348.
12. Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One. 2011;6(8):e23688.http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0023688. 13. Scherzer R, Estrella M, Li Y, Choi AI, Deeks SG, Grunfeld C, Shlipak MG. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012;26:867-875.http://www.natap.org/2012/HIV/Associatiotenofovirexposurekidney98985.pdf.
14. “Among those who discontinued tenofovir use, the time period following cessation was not significantly associated with either higher or lower risks of proteinuria (HR = 1.05 per year, 95% CI: 0.93-1.18, p = 0.41) or rapid decline (HR=1.05 per year, 95%CI: 0.94-1.16, p=0.42), although there was a marginal association of time off tenofovir with CKD (HR=1.22 per year, 95%CI: 0.99-1.50, p=0.055). All hazard ratios remained greater than unity, which suggests that the effects of tenofovir on kidney disease risk were not reversible following discontinuation” [13].
15. Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis. 2010;51:496-505.
16. Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS. 2012;26:825-831.http://www.natap.org/2012/HIV/Osteoporoticfractureriskassociatedwith989961.pdf.
17. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203:1791-1801. http://jid.oxfordjournals.org/content/203/12/1791.long.
18. Bonjoch A, Figueras M, Estany C, et al. High prevalence of and progression to low bone mineral density in HIV-infected patients: a longitudinal cohort study. AIDS. 2010;24:2827-2833.
19. Prejean J, Song R, Hernandez A, et al. Estimated HIV incidence in the United States, 2006-2009. PLoS One. 2011;6(8):e17502. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0017502.
20. Anderson P, Liu A, Buchbinder S, et al. Intracellular tenofovir-DP concentrations associated with PrEP efficacy in MSM from iPrEx. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 31LB.
21. Centers for Disease Control and Prevention. Interim guidance: Preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. MMWR. 2011;60(03);65-68.http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6003a1.htm?s_cid=mm6003a1_w.
22. PubMed Health. Isotretinoin. Last revision February 1, 2011. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000532/.

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Living With HIV  Should I Tell My Exercise Trainer I’m HIV Positive?
In addition to being HIV positive for the past 10 years, I also have seven heart stents and see my doctors regularly. I maintain as healthy a diet as possible and take all my medications. I turned 50 last year and decided to join a gym and get a trainer. I see the trainer two times a month and trust his knowledge. Knowing my HIV status might influence what kinds of exercises my trainer gives me to do, but I’m not sure I should disclose. How important is it for a trainer to know a client’s HIV-positive status? How much are trainers usually taught about HIV and body shape when they’re becoming certified?

Nelson Vergel responds in the “Nutrition and Exercise” forum

 How Can I Trust the Hospital That Broke My Confidentiality?
I stopped taking my HIV meds due to the fact that the staff at the hospital in my city where I go for care informed my employer that I was HIV positive, and I was fired. How can I trust any of the doctors or their recommendations when their hospital’s staff broke the law in this way?

Christa Douaihy, Esq., responds via the “Mental Health and HIV” forum
Mixed-Status Couples  How Can I Disclose to My Out-of-State Partner?
I’m a heterosexual HIV-positive woman. I met a guy while visiting out of my state. Since I’ve been back home he’s still been very engaged with me, and he wants a serious long-term relationship. I want to tell him I’m HIV positive before we get more involved, but find it difficult to tell him over the phone. Should I wait until we have a face-to-face meeting? What should I say? How can I start the conversation?

Shannon R. Southall responds in the “Safe Sex and HIV Prevention” forum
Insurance, Workplace & Legal Concerns  What’s the Best U.S. State for HIV Coverage and Benefits?
I’m a 52-year-old bi man and I’ve been HIV positive for 33 years. I was an HIV nurse during and after the onset of the epidemic. I have 700 T cells and I’ve worked with great doctors in the past. I’ve also lived in several U.S. states and had wildly different experiences accessing care in each place. I currently live in Riverside County, Calif., which has become a nightmare as far as coverage for indigent clients. Should I go back to a state where I got great care years ago? Do you have a sense of what the best states are for HIV care access nowadays?

Jacques Chambers, C.L.U., responds in the “Workplace and Insurance Issues” forum
Visual AIDS: Art from HIV-Positive Artists
Image from the May 2012 Visual AIDS gallery Detail from:
“In the Scheme of Things,” 1997
Jerry Hooten

Visit the May 2012 Visual AIDS Web Gallery to view our latest collection of art by HIV-positive artists! This month’s gallery, "Jungle Pussy," is curated by Yeni Mao.

HIV/AIDS Treatment  How Do I Keep My Kidneys Healthy?
I’m a 40-year-old man and I was diagnosed HIV positive almost two years ago. I was on Atripla (efavirenz/tenofovir/FTC) for 17 months and just switched to Isentress (raltegravir) and Truvada (tenofovir/FTC) about two months ago. My CD4 count is 440, my percentage is 20 and my viral load is undetectable. I’ve heard that Truvada can do irreversible damage to a person’s kidneys even if they stop taking that regimen. Is this true? How can I maintain my kidney health and reduce my risk of kidney damage on Truvada?

Benjamin Young, M.D., Ph.D., responds in the “Choosing Your Meds” forum


 When Is My HIV Med Regimen Likely to Fail?
I’m 59, HIV positive less than two years, my viral load is undetectable and my CD4 count is now over 1,600. I read that 75 percent of people living with HIV and taking meds will eventually learn they have to switch to different meds; the virus evolves and outsmarts their regimen. Is this accurate? How would age factor into this? How much time might I have before Isentress (raltegravir) and Truvada (tenofovir/FTC) stop working for me?

Nelson Vergel responds in the “Aging With HIV” forum

 How Should I Make the Switch From Sustiva to Reyataz?
I’ve been taking Atripla (efavirenz/tenofovir/FTC) since I was diagnosed with HIV in 2009. My lab results are great — my viral load is undetectable and my CD4 count is 720. However, I’m considering switching to Norvir (ritonavir), Reyataz (atazanavir) and Truvada (tenofovir/FTC) due to major depression from the Sustiva (efavirenz, Stocrin) in Atripla. I’ve heard that Sustiva remains in the body for a while after we stop taking it. How exactly should I proceed with the switch?

Joseph P. McGowan, M.D., F.A.C.P., responds in the “Choosing Your Meds” forum
Other Health Issues & HIV/AIDS  What Could Be Causing My Swollen Lymph Nodes?
A few weeks ago, I noticed a large lump in my right armpit. The fact that it didn’t ache concerned me, as I’ve always heard those are the ones to keep an eye on for things like cancer. My doctor was concerned, but then the swelling went down. All I can feel now is a few pea-sized nodes where the lump was. I’ve been told normal nodes should be that size and that you should be able to feel them, but I don’t feel any in my other armpit. I’ve read lymphoma can start off this way, with lymph nodes slowly swelling, and then it spreads. I’ve been feeling bad lately with fatigue and dizziness. Should I be worried?

Joseph P. McGowan, M.D., F.A.C.P., responds in the “Choosing Your Meds” forum

 Should I Find Out if There’s HIV in My Spinal Fluid?
I’m 45 years old and I’ve been HIV positive for 18 months. I currently take Epzicom (abacavir/3TC, Kivexa) and Sustiva (efavirenz, Stocrin) and have been doing very well, with most lab results in healthy ranges. As I get older I’ll be keeping an eye out for potential health issues, and dementia is one I’m particularly concerned about. I understand that it’s especially important for older HIVers to be on meds that have proven to easily pass through to the brain and spinal fluids to prevent HIV replication in those areas. What does current research suggest? Should I get my doctor to test my spinal fluid for HIV? Are these tests painful?

Benjamin Young, M.D., Ph.D., responds in the “Choosing Your Meds” forum
Connect With Others To Start or Not to Start HIV Meds?
(A recent post from the "Treatment & Side Effects" board)

So I am newly diagnosed with HIV and am trying to deal with this the best that I can. I visited my ID doctor today and my CD4 count was 680 and my viral load is 5,160, so he suggested that I start a regimen, so that my CD4 count doesn’t lower and cause me any issues. I am in great shape, with no symptoms (ever) of HIV. I’m so confused; should I start meds now? How have others made this decision?

I was diagnosed a few months ago, but have no idea when I contracted the virus; however I know from whom. …. I’d also love to hear people’s stories of dealing with HIV, since I don’t know anyone with HIV personally except my ID doctor. — melisss19195

Click here to join this discussion, or to start your own!

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Understanding HIV/AIDS Labs  Why Is My CD4 Count Staying so Low?
I’ve been taking HIV treatment since 2008. I always take my meds on time, I take care of myself and I’m planning to have a baby with my husband. I avoid stress, practice yoga, have limited my nights out, always get eight hours sleep, and eat healthily. All this being the case, why after five years is my CD4 count only 206? When I first got diagnosed my CD4 count was almost 70. Shouldn’t it have progressed more by now? What is going on?

Mark Holodniy, M.D., F.A.C.P., C.I.C., responds in the “Understanding Your Labs” forum
HIV Transmission  What’s the Difference Between Occupational and Non-Occupational PEP?
What’s the difference between the post-exposure prophylaxis (PEP) meds a person is given when they have a potential exposure to HIV at work versus “at play”? Could non-occupational PEP (nPEP) be less effective? Why are two meds sometimes prescribed while other times three or even four different meds are suggested?

Benjamin Young, M.D., Ph.D., responds in the “Choosing Your Meds” forum

 Is a Gay Man With Crohn’s Disease at Greater Risk for HIV?
Does having Crohn’s disease make it easier for a person to acquire HIV through unprotected receptive anal sex? If so, how does that increased risk work?

Mark Holodniy, M.D., F.A.C.P., C.I.C., responds in the “Understanding Your Labs” forum

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Fw: TheBodyPRO.com Newsletter: HIV/AIDS Headlines for Frontline Professionals

From: “The Body PRO” <news@thebodypro.com>
Date: 15 May 2012 16:02:34 -0400
To: <nelsonvergel@yahoo.com>
ReplyTo: “The Body PRO” <news@thebodypro.com>
Subject: TheBodyPRO.com Newsletter: HIV/AIDS Headlines for Frontline Professionals

If you have trouble reading this e-mail, you can read the online version at: www.thebodypro.com/newsletter.html
 
Welcome to The Body PRO Newsletter, a bi-weekly review of the latest breaking news and research in HIV medicine, aimed specifically at informing health care professionals.
May 15, 2012
In This Newsletter:
•  HIV CARE TODAY
medication approvalU.S. FDA Panel Recommends HIV “Quad” Drug for Approval
A U.S. Food and Drug Administration advisory panel last week recommended approval of the four-drug “Quad” pill for first-line HIV treatment. However, the panel warned about the potential for renal complications and expressed concern about the lack of female representation in the drug’s clinical trials.

Scott G. KitchenHuman Stem Cells Can Be Programmed to Find, Kill HIV, Researchers Say
“[A] team of UCLA researchers has now demonstrated that [genetically engineered human stem] cells can actually attack HIV-infected cells in a living organism,” the UCLA AIDS Institute announces.

anxietyAfrican Americans Less Likely to Adhere to HAART; Untreated Depression May Be a Factor
Fewer than 30% of African Americans living with HIV had “optimal” adherence in a recent study, compared to 40% of HIV-infected people of other races and ethnicities. Meanwhile, depression was found to be much more common among African Americans.

sleeping sheepInsomnia, Daytime Sleepiness Not More Likely Among HIV-Infected People, Study Suggests
Insomnia rates among those living with HIV and on HAART in the U.S. are no higher than the general population, despite sleep disturbances being a common complaint among HIV-infected people taking treatment, according to a study from the U.S. military.

More Headlines on HIV Care and Antiretroviral Therapy:


  Back to Top

•  HIV NEWS & VIEWS
Burger KingDid Burger King Fire One of Its Managers Because He Is HIV Infected?
Christopher Peña, a Burger King employee for seven years, and the Mexican American Legal Defense and Educational Fund filed a lawsuit against the fast food chain claiming that Peña was illegally fired because he is HIV positive.

leadershipEnding the Epidemic: A Call for Leadership
“The President and Secretary Clinton gave us the vision” for an AIDS-free generation, writes Paul Kawata of the National Minority AIDS Council. “Now it’s time for various federal departments to provide the substance to realize that vision and for Congress to appropriate the necessary resources to make it a reality.”

Barb CardellDear HIV Organizations: You Really Want to Help Us? Pay Us.
Barb Cardell dreads it when people ask her what she does for a living. “‘I am a professional volunteer,’ I usually respond. … What am I supposed to say? ‘I can’t work because 20 years ago I tested HIV positive, and just surviving was my full-time job?'”

Maura RiordanA Fire in the House: HIV/AIDS in the Deep South
“Having been active in the fight against HIV/AIDS for the past 25-plus years, I’ve seen plenty of life that is unfair, unjust and painful,” Maura Riordan of AIDS United writes. A recent trip to Alabama brought it all back: “What I have seen and heard is far too reminiscent of my early days in this fight,” she declares.

More News & Views Headlines:


  Back to Top

•  HIV/STD TRANSMISSION & EDUCATION
FDA Panel Recommends Approval of Tenofovir/Emtricitabine as Preventive Treatment for HIV
Late last week, an expert advisory panel recommended that the U.S. Food and Drug Administration approve tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis, also known as PrEP — but its recommendation was neither unanimous nor all-encompassing in terms of impacted populations.

Larry Bryant and Ingrid FloydHow to Get Heterosexual Black Men Involved in HIV Prevention, Part 2
We continue our in-depth roundtable discussion with a panel of experts about how U.S. society (and the HIV/AIDS community) can help heterosexual African-American men use condoms more, more openly discuss HIV, and value themselves and their health more highly.

condomsTo End HIV and Hepatitis C, We Have to Change the Conversation
It’s a common refrain: “Condoms make sex less enjoyable.” But is that really as true as many of us claim? “What about the idea of reframing sexual pleasure as including the absence of worry?” asks Dana Van Gorder, the head of Project Inform.

More Headlines on HIV/STD Transmission:


  Back to Top

•  THE PATIENT PERSPECTIVE: FEATURED ON THEBODY.COM
Dave R.Six Reasons Why People Skip Their HIV Meds
Taking antiretrovirals every day as prescribed isn’t the easiest thing to do, even in the once-daily treatment era. The reality is that everyday life brings with it obstacles that can stand between a patient and his or her treatment. This patient-focused slideshow discusses some of the common reasons why people skip doses and offers advice on how to resolve the issue.

Jamar RogersJamar Rogers Talks About Life After His Elimination (Audio)
May 1 marked the end of the road on The Voice for Jamar Rogers, an HIV-positive New Yorker who captured viewers’ hearts with emotional performances and his stirring story of redemption. He talked with POZ I AM Radio a few days after leaving the reality talent show.

The Positive ProjectUnder the Medicaid Microscope: Fighting for Assistance
Without Medicaid, Kat Griffith would never be able to afford her HIV treatment. But even though it keeps her alive, renewing her Medicaid authorization each year is a stunningly miserable experience.

Dave R.Dave R: “Dear Dave …”: The Virus Writes Back
“You knew all about me before we met … How many friends had I killed, with you watching me do it and yet still determined to get into bed with me eventually? Oh please, don’t tell me you never meant for this to happen!”

Sonia RastogiAs a Young Woman With HIV, Can I Still Reach for the American Dream?
“Is the American Dream of life, liberty and the pursuit of happiness really achievable for HIV-positive women?” Sonia Rastogi asks. “[HIV] does not have to be a disease of crisis, despair and shame. Yet, it is. It is because HIV runs the well-worn path of gender inequality.”
  Back to Top

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Also Worth Noting

2011: The Year in Review •  Top HIV/AIDS-Related Clinical Developments of 2011

David Wohl, M.D., takes an in-depth look at the past year’s most critical HIV-related studies, and explains how each may change the manner in which we practice HIV prevention or treatment in 2012 and beyond.

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