NIH Discontinues Immunizations in HIV Vaccine Study

needle01

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, will stop administering injections in its HVTN 505 clinical trial of an investigational HIV vaccine regimen because an independent data and safety monitoring board (DSMB) found during a scheduled interim review that the vaccine regimen did not prevent HIV infection nor reduce viral load (the amount of HIV in the blood) among vaccine recipients who became infected with HIV.

The HVTN 505 study began in 2009 and was testing an investigational prime-boost vaccine regimen developed by NIAID’s Vaccine Research Center. The Phase IIb study, conducted by the NIAID-funded HIV Vaccine Trials Network (HVTN), was designed to determine whether the vaccine regimen could prevent HIV infection and/or reduce the amount of virus in the blood of vaccine recipients who became infected with HIV.

The investigational HIV vaccine regimen involved a series of three immunizations over the course of eight weeks, beginning with a DNA-based vaccine designed to prime the immune system. The DNA priming vaccine contained genetic material expressing antigens representing proteins from both the surface and internal structures of HIV. Immunizations with the priming vaccine were followed by a single injection at week 24 with a recombinant vaccine (the booster vaccine) based on a weakened adenovirus type 5 (Ad 5). The adenovirus was used as a vector, or carrier, of genetic material expressing a matching set of HIV antigens. Structures from all three major HIV clades, or subtypes, were included. Adenoviruses are a common cold virus, but the Ad5 virus used in the study’s vaccine regimen was disabled so that it could not cause a cold or other respiratory illness. The two investigational vaccines tested in HVTN 505 cannot cause HIV infection because neither contains live or weakened versions of HIV.

The HVTN 505 study enrolled 2,504 volunteers at 21 sites in 19 U.S. cities. The study population consisted of men who have sex with men and transgender people who have sex with men. In its April 22 interim review, the DSMB examined the information gathered from 1,250 volunteers who received the investigational vaccine regimen and 1,244 volunteers who received the placebo vaccine. The primary analysis looked at volunteers who were diagnosed with HIV infection after having been in the study a minimum of 28 weeks. This was done to enable enough time for the vaccine regimen to be given and stimulate an immune response. In this analysis, 27 HIV infections occurred among the vaccine recipients, and 21 HIV infections occurred among the placebo vaccine recipients. Among volunteers who became HIV-infected during the first 28 weeks of the study, 14 cases of HIV infection occurred among those who received the investigational vaccine regimen, and 9 HIV infections occurred among the placebo vaccine recipients. Overall in the study from the day of enrollment through the month 24 study visit, a total of 41 cases of HIV infection occurred in the volunteers who received the investigational vaccine regimen and 30 cases of HIV infection occurred among the placebo vaccine recipients.

Additionally, the DSMB found that the vaccine failed to reduce viral load among volunteers who acquired HIV infection at least 28 weeks after entering the study and who had been followed for at least 20 weeks after diagnosis. There were 30 participants with measurable viral load (15 vaccine recipients; 15 placebo recipients).

Based on these findings, the DSMB recommended that no further vaccinations with the investigational vaccine regimen be administered. As the trial’s sponsor, NIAID concurred with the DSMB’s recommendation and has instructed all HVTN 505 study sites to immediately cease administering injections but continue follow-up with study participants to further evaluate the trial data.

It should be noted that there was a non-statistically significant increase in HIV acquisition among volunteers in the investigational vaccine group compared to those in the placebo group. It is not clear why this occurred and further analysis is needed to draw any firm conclusions. Based on the finding, the DSMB recommended closer follow-up of participants beyond their month 24 study visit. NIAID concurred, and will, in concert with the study investigators, be amending the study protocol to allow for closer, extended follow up of the vaccine recipients.

As with all NIAID-sponsored HIV prevention trials, the HVTN 505 participants were offered extensive counseling on how to reduce their risk of becoming HIV-infected and provided free condoms. As an added precaution, study participants were required at time of enrollment to be circumcised and free of antibodies to Ad5. These precautions were taken in light of an HIV vaccine clinical trial, known as the Step Study, which found in 2007 an increased number of HIV infections among vaccine recipients, particularly those who were not circumcised and/or had Ad5 antibodies.

NIAID and the HVTN 505 study team are working to thoroughly analyze the study data to better understand why the vaccine did not work and to guide future vaccine development efforts. Detailed scientific findings will be made publicly available as soon as possible.

Study investigators at each of the 21 clinical trial sites have been informed of the decision to stop immunizations in the HVTN 505 study and are contacting study volunteers to inform them of the developments. Study volunteers are being asked to report to their specific clinic sites over the next few weeks to find out whether they received the investigational vaccines or placebo. Individuals who became HIV-infected during the trial were referred to local services for appropriate medical care and treatment. The study investigators will continue following all study participants for five years from the time of enrollment.

NIAID remains committed to the pursuit of a highly effective, preventive HIV vaccine as part of a multifaceted HIV prevention research program. For more information about the HVTN 505 study, please see the updated Questions and Answers. To learn about NIAID’s HIV vaccine research, please see the HIV vaccine section of the NIAID website.

Advertisements

NIH researchers identify pathway that may protect against cocaine addiction

A  study by researchers at the National Institutes of Health gives insight into  changes in the reward circuitry of the brain that may provide resistance  against cocaine addiction. Scientists found that strengthening signaling along  a neural pathway that runs through the nucleus accumbens — a region of the  brain involved in motivation, pleasure, and addiction — can reduce  cocaine-seeking behavior in mice.

Research  suggests that about 1 in 5 people who use cocaine will become addicted, but it  remains unclear why certain people are more vulnerable to drug addiction than  others.

An illustration of the cross-section of a mouse brain

A cross-section of the mouse brain. Using lasers, researchers stimulated a specific subtype of neurons in the nucleus accumbens (shown in green) and found that it curbed compulsive cocaine use in mice.

“A  key step in understanding addiction and advancing treatment is to identify the  differences in brain connectivity between subjects that compulsively take  cocaine and those who do not,” said Ken Warren, Ph.D., acting director of the  National Institute on Alcohol Abuse and Alcoholism (NIAAA). Researchers at  NIAAA, part of NIH, conducted the study.

“Until  now, most efforts have focused on finding traits associated with vulnerability  to develop compulsive cocaine use. However, identifying mechanisms that promote  resilience may prove to have more therapeutic value,” said the paper’s senior  author, Veronica Alvarez, Ph.D., acting chief of the Section on Neuronal  Structure in the NIAAA Laboratory for Integrative Neuroscience.         The study is available on the  Nature Neuroscience website ahead of print.

In  the study, mice were conditioned to receive an intravenous dose of cocaine each  time they poked their nose into a hole in their enclosure. Cocaine was then  made unavailable for periods of time during the day. Some of the mice would  stop seeking the drug once it was removed while others would obsessively  continue to poke the hole in an effort to obtain the drug.

Mice  that quickly stopped seeking the drug were found to have stronger connections  along the indirect pathway — a neural tract that forms indirect projections  into the midbrain and contains cells called medium spiny neurons expressing  dopamine D2 receptors (D2-MSNs). A parallel pathway — known as the direct  pathway — forms direct projections into the midbrain neurons and contains  medium spiny neurons expressing D1 receptors (D1-MSNs). These two pathways are  thought to work together in complementary but sometimes opposing ways to affect  behavior.

“We were very surprised  by the results of the study because we were originally looking for  vulnerability factors for developing compulsive drug use,” said Dr. Alvarez.  “Instead, we found changes that only happened in subjects that show a  resilience to becoming compulsive drug users. Resilient mice had a strong  inhibitory circuit that allowed them to exert better control over their drug intake.”

To  test this observation, researchers used lasers to activate individual neurons,  and found that stimulating D2-MSNs in the nucleus accumbens decreased cocaine  seeking in the mice. Blocking D2-MSN signaling with a chemical process  increased motivation to obtain cocaine.

“This  research advances our understanding of how the recruitment, activation and the  interaction among brain circuits can either restrain or increase motivation to  take drugs,” said David Shurtleff, Ph.D. acting deputy director of the National  Institute on Drug Abuse.

Previous  studies have shown that people with lower levels of dopamine D2 receptors in  the striatum, a brain region associated with reward and working memory, are  more likely to develop compulsive behaviors toward stimulant drugs.

Dopamine  is a key neurotransmitter involved in reward-based learning and addiction.  Cocaine disrupts communication between neurons at the synapse, the small  junction between nerve cells, by blocking the reabsorption of dopamine into the  transmitting neuron. As a result, dopamine continues to stimulate the receiving  neuron, causing feelings of alertness and euphoria.

The National Institute on Alcohol Abuse and Alcoholism,  part of the National Institutes of Health, is the primary U.S. agency for  conducting and supporting research on the causes, consequences, prevention, and  treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also  disseminates research findings to general, professional, and academic  audiences. Additional alcohol research information and publications are  available at http://www.niaaa.nih.gov.

 

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers  and is a component of the U.S. Department of Health and Human Services. NIH  is the primary federal agency conducting and supporting basic, clinical, and  translational medical research, and is investigating the causes, treatments,  and cures for both common and rare diseases. For more information about NIH  and its programs, visit http://www.nih.gov.

NIH…Turning Discovery Into Health ®

CD4 count affects non-AIDS risk in people yet to start antiretrovirals

 

A CD4 count below 350 more than doubled the risk of serious non-AIDS diseases in HIV-positive people who had not begun antiretroviral therapy [1]. Viral load in untreated people did not appear to affect risk of non-AIDS diseases in this 13,000-person ATHENA cohort analysis in the Netherlands.
 
Research has linked certain non-AIDS diseases to low CD4 count or high viral load in people taking antiretroviral therapy. But little is known about the impact of CD4 count and viral load on these morbidities in HIV-positive people who have yet to start antiretrovirals. To address these questions, ATHENA cohort investigators conducted this study of antiretroviral-naive cohort members.
 
This ATHENA analysis included 13,077 people in the Netherlands diagnosed with HIV in 1998 or later and not yet taking antiretrovirals. The researchers counted new diagnoses of major cardiovascular diseases (myocardial infarction, stroke, invasive coronary procedures), liver fibrosis or cirrhosis, and non-AIDS malignancies. A composite endpoint included diagnoses in all three disease clusters. The ATHENA team considered non-AIDS conditions that developed from the time of a cohort member’s first CD4 count onwards. Follow-up continued until antiretroviral therapy began or the last follow-up visit.
 
The analysis included 18,641 person-years of follow-up. During that time, a new non-AIDS condition developed in 208 people (1.6%). Five people had two or more non-AIDS diagnoses. There were 53 cardiovascular events, 79 cases of liver fibrosis/cirrhosis, and 82 non-AIDS malignancies.
 
Overall incidence of combined events reached almost 6 per 100 person-years in people with a CD4 count below 200, meaning that 6 of 100 people had one of these diagnoses every year. (See Figure 1 in the poster linked below.) Among people with a sub-200 CD4 count, incidence of non-AIDS malignancies or cardiovascular disease was about 2 per 100 person-years, while liver fibrosis/cirrhosis incidence lay slightly below that. Among people with 200 to 349 CD4 cells, composite incidence of these non-AIDS conditions lay between 1 and 2 per 100 person-years, while incidence of non-AIDS malignancy and liver fibrosis approached 1 per 100 person-years.
 
The investigators used a Poisson regression model to assess associations between time-updated CD4 count and viral load and the composite non-AIDS endpoint. The model was adjusted for demographics, smoking history, alcohol use, CDC disease stage, hepatitis B or C, diabetes, and hypertension.
 
Compared with a CD4 count of 500 or higher, a count below 200 more than quadrupled the risk of the composite non-AIDS endpoint, while a count between 200 and 349 more than doubled the risk. A count between 350 and 499 did not significantly affect risk of the composite endpoint:
 
Relative risk (RR) of the composite non-AIDS endpoint (and 95% confidence intervals):
— Below 200 CD4s: RR 4.36 (2.83 to 6.73)
— 200 to 349 CD4s: RR 2.13 (1.45 to 3.14)
— 350 to 499 CD4s: RR 1.23 (0.85 to 1.78
— 500 or more CD4s: Reference
 
In contrast, time-updated viral load did not affect chances of the composite non-AIDS endpoint.
 
“In persons not yet receiving combination antiretrovirals therapy,” the ATHENA team concluded, “a more severe degree of immunodeficiency rather than HIV RNA appears to be associated with an overall risk of our composite non-AIDS event endpoint.” They call for larger studies to assess potential associations between individual non-AIDS diseases, CD4 count, and viral load in untreated people.
 By Mark Mascolini

Aging with HIV a unique health challenge

 

LIFE HEALTH-SRS-AGING-HIV 1 CC

  • Joey Wever, 63, is HIV-positive. Thanks to antiretroviral treatments, the life expectancy of people with HIV is increasing with many living to their 50s, 60s and older.

WALNUT CREEK, Calif. —  Not long after Bob Reed learned in 1986 that he had AIDS, he watched 20 of his friends die from the disease as it ravaged his body and he battled to survive.

Today, as he sits in his Saratoga, Calif., home feeling better than he has in years, he ponders a question no one can answer.

“Why did I make it and other people didn’t?” he asks. “There’s a part of me that has a little bit of survivor guilt.”

As the epidemic enters its fourth decade, Reed, 57, is among a growing number of people who are living with HIV or AIDS into their 50s, 60s and beyond, surviving with a new generation of medications that have greatly increased life expectancy.

Before the mid-1990s, three-quarters of people infected with HIV, the virus that causes AIDS, died within 10 years. Now, for those who get early diagnosis and prompt treatment, nearly normal life spans are possible.

About 1.1 million American adults and teenagers were living with HIV infection in 2009, and 17 percent of them were 55 or older, according to the latest estimate.

Still, aging with HIV has unique health challenges. Some people grapple with chronic conditions typically seen in those who are 20 years older — heart disease, bone loss and kidney damage. Others deal with premature aging of an immune system that has fought the infection for years.

And scientists are just beginning to explore the long-term effects of a complex cocktail of HIV medications, including how they interact with other drugs that aging people often take.

Despite the challenges, many who have worked with HIV-infected people for years — and seen so many die — say aging with AIDS is survival.

“This is a wonderful problem to have,” said Alvan Quamina, executive director of AIDS Project East Bay.

Reed spent nearly half of his life assuming he was about to die.

He had a stroke in 1994 and now has heart disease that led doctors to install two stents in his arteries.

His toughest year came in 2005 when a painful stomach infection caused him to vomit almost daily and the 6-foot-1 former nurse’s weight dramatically dropped to 130 pounds. He had a feeding tube in his chest for months.

“He spent much of the year near death,” recalled Phil Hofford, his partner of 21 years. “We were pretty much making final plans a couple times during that period.”

It wasn’t until 2009 that a newly available medication resolved his stomach infection “and saved my life,” Reed said.

In November, he felt well enough to start working again. He now does HIV test counseling at the Billy DeFrank LGBT Community Center in San Jose, Calif., and weighs a healthy 182 pounds.

“He’s coming back to life,” Hofford said. “Suddenly he’s waking up, like Rip Van Winkle.”

Yet their home is a constant reminder of the ravages of the disease.

Its previous owner took in people who had AIDS during the early days of the epidemic. More than 20 people died in the single-story house near the San Jose border. But Reed and Hofford consider living there uplifting.

“To me, it’s pretty awe-inspiring to know what was going on in that house,” Hofford said. “There has been more love in that house for the people that passed on than most houses see in a lifetime.”

Reed said he has no idea why he survived when so many others did not.

“Whenever my T-cells (white blood cells that help the body fight disease) were the lowest and hope was the least, a new medication would come out,” he said. “I’m just one of the luckiest people I know.”

Those who look at Joey Wever these days would never guess he has HIV.

The 63-year-old Oakland, Calif., resident learned he was infected in 1996, after an eye doctor noticed his eyes were damaged and asked if he had been given an AIDS test.

“I lost about 40 percent of my peripheral vision on the right side,” said the former X-ray and ultrasound technician.

But by 2000, he had improved enough to take a full-time job with the city of Berkeley, Calif., as a social worker for Meals on Wheels. He was so busy, however, that he neglected his regimen of pills every eight hours.

He developed a resistance to the medications and at 5 feet 8, watched his weight plummet from 155 pounds to 128.

“I saw my reflection on glass and I even scared myself,” he said.

His doctor changed his medications and his health improved, but his life really turned around when drugs known as protease inhibitors came out.

“I feel so energetic and I’m more involved in the community,” he said during a recent interview in his apartment, as his four colorful lovebirds chirped away.

The medications for those infected with HIV have greatly improved, but questions remain about the long-term effects.

“Most of the studies were initially done on much younger patients because that’s who was more likely to be infected,” said Michael Horberg, Kaiser Permanente’s national director of HIV/AIDS.

“So we don’t know how all the antiretrovirals are going to work as patients get older and have been on these meds cumulatively many more years.”

The epidemic is by no means over: In 2011, nearly 50,000 new HIV infections were identified in the United States and more than 32,000 people were newly diagnosed with AIDS, according to the latest national Centers for Disease Control and Prevention report.

The early aging of people with HIV may not lead to more gray hair and wrinkles, but it becomes apparent in their blood and immune systems, said Mark Holodniy, an infectious disease professor at Stanford University and director of public health surveillance for the Department of Veterans Affairs.

“And even when people are on effective treatment and controlling the virus,” Holodniy said, “there is still an ongoing inflammatory response in the body that seems to wreak havoc. Some of the problems that you might expect in people that are 60 or 70 years old, you’re now seeing in people that are 40 or 50.”

  • By Sandy Kleffman

Contra Costa Times

Published Tuesday, March 26, 2013, at  8:58 a.m.

Drug Side Effects

o learn all the details about each drug’s potential side effects, see the drug’s page or get out a magnifying glass and read that tiny print in the Patient Information insert that comes with your medications. Remember that side effects may or may not occur. Some are more common than others, and individuals react differently to the same drug. A drug regimen cannot be chosen solely on the basis of potential side effects. Pay attention to any changes that you notice with your body and discuss any symptoms, however minor, with your health care providers, including your pharmacist, since small reactions may become serious. There may also be management techniques for the side effect. Listed below are the most common side effects for each class of drugs as well as for therapy as a whole. Remember, not every drug in each class will have every side effect.

ART   There are potential side effects (good and bad) associated with HIV therapy itself. Good: Taking ART (antiretroviral therapy) can make people less likely to transmit HIV if they have an undetectable viral load (less than 50 copies/mL), according to DHHS HIV treatment guidelines updated last year. There should be no other sexually transmitted infection present among sex partners, HIV-positive or not, as it would increase risk of transmission. Of note, HIV can be undetectable in blood levels but detectable in genital fluids, thereby increasing risk of transmission. For more details, go to http://www.aidsinfo.nih.gov. Bad: Immune Reconstitution Inflammatory Syndrome (IRIS) may occur as the immune system regains strength; signs and symptoms of inflammation from previous infections may occur soon after ART is initiated. Report symptoms of illnesses such as shingles and tuberculosis (TB) to a health care provider right away.

*Click on the name of each drug  for further details, or refer to the  manufacturer’s package insert for a comprehensive list of potential drug side  effects. Remember that side effects may or may not occur. Some are more common  than others, and individuals react differently to the same drug. A drug regimen  cannot be chosen solely on the basis of minimal potential for side effects.  Discuss any symptoms, however minor, with your health care providers, including  your pharmacist, since small reactions may become serious. There may also be  management techniques for side effects.

Nucleoside reverse transcriptase inhibitors (NRTIs)
Potential drug class side effects Rare but potentially serious side effects with all NRTIs: Enlarged, fatty liver and lactic acidosis (accumulation of lactate in the blood and abnormal acid-base balance). Lactic acidosis may cause persistent fatigue, abdominal pain or distension, nausea/vomiting, and difficulty breathing.
Combivir (lamivudine / zidovudine) See Epivir and Retrovir.
Emtriva (emtricitabine, or FTC) A very tolerable drug, but side effects may include headache, diarrhea,    nausea, and rash. Darkening of the skin on the palms and the soles of   the feet  has also been reported.
Epivir (lamivudine, or 3TC) A very tolerable drug, but side effects may include headache, nausea,  vomiting, diarrhea, fever, fatigue, hair loss, insomnia, malaise, nasal  symptoms, and cough.
Epzicom  (abacavir / lamivudine) See Ziagen and Epivir.
Retrovir (zidovudine, AZT, or ZDV) Headaches, fever, chills, muscle soreness and/or damage, fatigue,  nausea, lipodystrophy, fingernail discoloration, anemia (low red blood cell  count), and neutropenia (low white blood cell count).
Trizivir (abacavir / lamivudine / zidovudine) See Ziagen, Epivir, and Retrovir
Truvada  (emtricitabine /  tenofovir DF) See Emtriva, and Viread. Abdominal  distension/pain.
Videx EC (didanosine, or ddI) Peripheral  neuropathy, upset stomach, diarrhea, headache, pancreatitis (inflammation of  the pancreas), eye changes and optic neuritis, increased uric acid levels,  insomnia, and body fat redistribution.
Viread (tenofovir DF,  or TDF) Overall  fairly well tolerated; however, side effects may include nausea, diarrhea,  vomiting, flatulence (gas), bone changes, kidney toxicities, decreased bone  mineral density, and low blood phosphate.
Zerit (stavudine, or d4T) Headache, diarrhea, nausea, rash, peripheral neuropathy, lipoatrophy  (including facial wasting), mitochondrial toxicities (a variety of symptoms  caused by cell damage), and elevated cholesterol levels.
Ziagen (abacavir, or ABC) Hypersensitivity  reaction, nausea, vomiting, diarrhea, fatigue, headache, fever, rash, and loss  of appetite.
Protease inhibitors (PIs)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Potential drug class side effects Common with NNRTIs is rash.
Edurant (rilpivirine, or RPV) Insomnia,  headache, rash, and depressive disorders.
Intelence (etravirine, or ETR) Rash,  diarrhea, nausea, nasopharyngitis (symptoms like a common cold), headache,  hypersensitivity, and increased liver enzyme levels.
Rescriptor (delavirdine, or DLV) Increased  liver enzyme levels and itchy skin or rash.
Sustiva (efavirenz, or EFV) Central  nervous system (CNS) and psychiatric symptoms. Rash, nausea, vomiting,  diarrhea, fever, insomnia, and increases in triglycerides, bad cholesterol  (LDL), good cholesterol (HDL), and liver enzyme levels. False positive tests  for marijuana. Birth defects.
Viramune XR (nevirapine, or NVP) Headache,  nausea, vomiting, fever, rash, Stevens-Johnson syndrome, increased liver enzyme  levels, liver damage, and drug-induced hepatitis.
Potential drug class side effects Seen with all PIs except Prezista and unboosted Reyataz (and sometimes boosted Reyataz as well): Increased levels of cholesterol and triglycerides, which may be associated with an increased risk of heart disease. Other possible side effects are lipodystrophy (body fat changes, including thinning of the face, arms, and legs, with or without fat accumulation in the stomach, breasts, and upper back), onset of new cases or worsening of diabetes (see your doctor promptly), and increased bleeding in hemophiliacs.
Aptivus (tipranavir, or TPV) (must be taken with  Norvir) Mild diarrhea, nausea, vomiting, and abdominal pain. Headaches, fever,  fatigue, dry mouth, rash (including sensitivity to sun), dizziness, liver  toxicity, and bleeding in the brain. Aptivus has a sulfa component; use with  caution in patients with allergies to sulfa drugs. Also see Norvir.
Crixivan (indinavir sulfate, or IDV) Headache,  fatigue or weakness, malaise, nausea, diarrhea, stomach pain, loss of appetite,  txtBlulowing of skin/eyes, changed skin color, dry mouth/sore throat, taste  changes, painful urination, indigestion, joint pain, hives, liver toxicity,  kidney stones, increased bilirubin, itchy/dry skin, ingrown toenails, and hair  loss.
Invirase (saquinavir, or SQV) (must be taken with  Norvir) Diarrhea, abdominal discomfort, vomiting, and nausea. Also see Norvir.
Kaletra (lopinavir / ritonavir, or LPV / r) Rash,  diarrhea, nausea, vomiting, stomach pain, headache, muscle weakness, increased  cholesterol and triglycerides, and increased liver enzyme levels. Also see Norvir.
Lexiva (fosamprenavir calcium, or FPV) Nausea, rash, diarrhea, headache, vomiting, fatigue, and abdominal pain.  Lexiva has a sulfa component; use with caution in patients with allergies to  sulfa drugs.
Norvir (ritonavir, or RTV) Weakness,  stomach pain, upset stomach, tingling/numbness around the mouth, hands or feet,  loss of appetite, taste changes, weight loss, headache, dizziness,  pancreatitis, alcohol intolerance, liver problems, increased muscle enzyme  levels, and uric acid.
Prezista (darunavir, or DRV) (must be taken with  Norvir) Rash,  diarrhea, nausea, headache, abdominal pain, and increased liver enzyme levels.  Prezista has a sulfa component; use with caution in patients with allergies to  sulfa drugs.  Also see Norvir.
Reyataz (atazanavir sulfate, or ATV) Dizziness,  lightheadedness, rash, kidney stones, and elevated liver enzyme levels,  including elevated levels of unconjugated bilirubin.
Viracept  (nelfinavir, or NFV) Diarrhea,  stomach discomfort, nausea, gas, weakness, and rash.
Integrase inhibitors (INSTIs)
Potential drug class side effects At press time, Isentress was the only stand-alone integrase inhibitor on the market, but Stribild, approved last year, contains elvitegravir. Dolutegravir and elvitegravir are expected to be FDA approved in 2013. No drug class side effects known to date.
Isentress (raltegravir, or RAL) A very tolerable drug, but side effects may include diarrhea, nausea,  vomiting, headache, fever, abdominal pain, fatigue, weakness, dizziness,  lipodystrophy, increased levels of liver enzymes and creatine kinase, allergic  reaction, and cerebellar ataxia.
dolutegravir (or DTG) (investigational drug) Seen  in clinical study: nausea, diarrhea, headache, dizziness, fatigue, weakness,  and upset stomach or indigestion. Available data is limited due to  investigational status at press time.
elvitegravir (or EVG) (investigational drug) Seen  in clinical study: diarrhea, upper respiratory tract infection, bronchitis,  back pain, depression, sinusitis, joint pain, nausea, and urinary tract  infection. Available data is limited due to investigational status at press time.
Entry inhibitors
Potential drug class side effects No drug class side effects known to date.
Fuzeon (enfuvirtide, T-20, ENF) Injection  site reactions (ISRs), pneumonia, diarrhea, nausea, and fatigue.  Hypersensitivity reactions are possible.
Selzentry (maraviroc, or MVC) Cough,  fever, cold, rash, muscle and joint pain, stomach pain, dizziness, liver  toxicity, allergic reaction, low blood pressure, and possible increased risk of  infections and cancer.
Single-tablet regimens (STRs)
Potential drug class side effects Because each pill contains a combination of medicines from different drug classes, the best thing to do is look up each drug in the pill.
Atripla (efavirenz / emtricitabine / tenofovir DF) See Sustiva and Truvada (Emtriva and Viread). Atripla dose cannot  be adjusted for people with kidney problems. Nausea, diarrhea, rash, insomnia,  abnormal dreams, and depressive disorders.
Complera (rilpivirine / emtricitabine / tenofovir DF) See Edurant and Truvada (Emtriva and Viread). Complera dose cannot  be adjusted for people with kidney problems. Insomnia, headache, nausea,  dizziness, rash, abnormal dreams, and depressive disorders.
The “Quad” (elvitegravir / cobicistat / emtricitabine / tenofovir DF)  (investigational drug) See elvitegravir, cobicistat, and Truvada (Emtriva and Viread). The Quad dose cannot  be adjusted for people with kidney problems. Nausea, diarrhea, and rash.  Available data is limited due to investigational status at press time.
PK enhancer
Potential drug class side effects No drug class side effects known to date.
cobicistat (or COBI) (investigational drug) Seen  in clinical study: diarrhea, nausea, lipid elevations (increases in cholesterol  and triglycerides), creatine kinase, red blood cells in urine, increased serum  creatinine, and decreased estimated glomerular filtration rate (e-GFR).  Available data is limited due to investigational status at press time.

top

Mapping out a strategy

What lies ahead - Trends in HIV treatment and care - By Joel Gallant, MD, MPH

Mapping out a strategy.

o You have your Drug Guide, which contains a  wealth of information, but where exactly should you start? Just like any map,  you’ll need a reference tool to help chart your course. Here are a few things  you might find useful when navigating this year’s Drug Guide.

Medications  that are included in the HIV Drug Guide are only those drugs in the U.S. that  are either FDA approved or expected to be approved in the coming year, as well  as those that are available through an expanded access program (EAP).

Drugs should always be taken in  combination when treating HIV, by pairing medications from two or  more drug classes (for example, a boosted protease inhibitor along with two  non-nukes). Some drug combinations are available as one pill (see single-tablet  regimen below). To learn more about how the different drug classes work, go to  positivelyaware.com/drugclass and see the  illustration above.

Drugs are color-coded by class and are listed alphabetically by brand  name (capitalized), or generic name (lower case) if not yet FDA approved. The  brand name is listed first, then followed by   the generic name (scientific designation), and any abbreviations.  Example: Isentress  is the brand name, raltegravir is the generic name, and RAL is the  abbreviation. When a drug is available as a generic, it will be indicated in  the “Standard dose” section of the drug’s page, and also on the pull-out drug  chart.

When a drug is available in generic  form, or when it is part of a multi-drug combination, it  will be referred to by its generic name. Example: Retrovir, commonly known  as AZT, is available in generic form as zidovudine. Therefore, on the Combivir page, it is  referred to as zidovudine since it’s part of Combivir. However, you  should still look for the Retrovir page to find information on  zidovudine. Note: In the doctor’s and activist’s comments on each drug page,  this rule does not apply. Also, in the “Interactions” section of each page,  drugs are referred to by their most-used name, as determined by the pharmacist.  Lastly, Viread’s generic name will appear as  “tenofovir DF” or “tenofovir.”

A  fixed  dose combination (FDC) combines two or more drugs in one tablet, such as Epzicom  (lamivudine/abacavir). A single-tablet regimen (STR) contains drugs from different drug  classes and is a complete regimen in one pill, such as Atripla (efavirenz/emtricitabine/tenofovir). Atripla, Complera, and Stribild  are the three single-tablet regimens that are now available, with approval of  another STR, “572-Trii,”  expected sometime in 2014.

The  Average  Wholesale Price (AWP)  is used by pharmacies and other buyers to negotiate the amount they pay for  drugs. The AWP is included as a way to compare costs of the drugs. It is not  necessarily what you would pay if you had to pay the full retail price.

drug-class  side effect page,  which lists potential side effects that can be expected for each drug within an  entire drug class, has been included in the Drug Guide. The drug  interaction chart makes it easier to identify some of the most important drug interactions that  you need to be aware of and look out for. This year the chart is available exclusively  online at  positivelyaware.com/interactions. Always refer to the individual drug pages,  package insert, or talk to your physician or pharmacist for more information.

Paying for your medications can often be a  challenge, but there are programs that can help cover all or part of the costs  and facilitate access. For a list of drug co-pay and patient assistance  programs, see “Don’t break the bank.” This year we’ve  also added information on programs for drugs used to treat not only HIV but  also hepatitis B and C, as well as several other drugs that are important for  people living with HIV.

The HIV treatment guidelines are established by a panel of experts  in conjunction with the Department of Health and Human Services (DHHS) to help  physicians and patients inform their treatment decisions. They’re available as  a downloadable PDF at http://www.aidsinfo.nih.gov, or go to  http://www.positivelyaware.com/guidelines.

You  can easily read up on each drug online by entering the drug name  after our URL. For example, you’ll find the Drug Guide’s page for Prezista by typing http://www.positivelyaware.com/prezista; these unique URLs  are also seen at the bottom of each drug’s page.

Timing and T-Cells

Editors Note by Jeff Berry

Timing and T-Cells – The evolution of when to start treatment-through on doctor’s eyes

ver since the first antiretrovirals were approved, one of the most vexing questions for  patients and doctors has been when to start therapy. In the past two years, a  host of new data has been released that is bringing us closer to a time when  therapy can be offered to everyone with HIV. I would like to share with you the  evolution in my own thinking which may help you make a decision.

When  to start has been compared to a pendulum swinging back and forth, with higher  and lower limits set for the decision on when to initiate antiretroviral  therapy (ART). A pendulum, however, swings back and forth between fixed points.  The debate about “when to start” has been more like a playground swing hanging  from a decision framework made up of CD4 counts and viral loads. With one major  exception, that swing has consistently moved higher, suggesting initiation of  treatment earlier and earlier in the disease process.

Making the decision has meant weighing the pros and cons  of treatment. On the pro side has been our desire to control and possibly cure  the disease. HIV has been one of the only diseases in modern medicine that is  not treated immediately upon discovery, one we wait years or even decades to  treat.

On  the negative side rest much heavier concerns, including drug toxicities, cost  of medication, the need for perfect adherence, denial of access by insurance  companies and governments, and lack of research data. For most of the last 25  years, the swing swung back towards waiting to start therapy. But while we  waited, our thinking evolved.

In  the beginning

When  AZT was first available, it was only approved for patients who had experienced  an opportunistic infection. After so many years without any therapy, it quickly  became clear, however, that people who were suffering from other complications  of HIV were going to demand access to the drug. In retrospect, most of the  people getting it in those days had very, very low CD4 counts, probably less  than 50. We all know now that any benefit from AZT was probably limited to a  six-month increase in survival in those very advanced people. More drugs became  available during the late 1980s and early 1990s and our comfort level in  treating people increased. We progressed to treating everyone with fewer than  200 CD4 cells/mm3. In 1993, the case definition was changed so that  a low CD4 count alone meant an AIDS diagnosis. Part of the impetus for this was  to ensure access for people with low CD4 counts who weren’t yet ill with  infections.

HAART  arrives

The 200 CD4 limit remained for many years, and in fact,  remained in place in the World Health Organization guidelines until 2010. In  the U.S. and Western Europe, the 200 CD4 limit began to be called into question  with the advent of highly active antiretroviral therapy (HAART) in the late  1990s. There was a great deal of excitement about the benefits we were seeing  in those starting on the triple combination cocktail, despite the very serious  side effects and complications of those early treatments. People with CD4  counts over 200 began wanting access to the medications. We also understood  more about the dynamics of HIV infection. It became clear that rather than  there being a “latent” period when the virus was controlled and nothing much  was happening, HIV infection was, instead, a very dynamic process.

By  the late ’90s, studies were being initiated in people with higher CD4 counts  and there was interest in treating early infection. We had clear-cut data from  controlled clinical trials and observational studies that the 200 CD4 limit was  important, but many of those caught in the middle (not in acute or early  infection but above the 200 CD4 level) became increasingly uncomfortable with  not being treated. There were serious discussions about moving the bar up to  500, with David Ho and others advocating that we “hit hard, hit early.” Not  waiting for studies to be completed, many patients, beginning with the activist  community, put their bodies on the line to test this in practice. And so the  swing got a push and swung upward.

By  the turn of the century, the side effects and complications of HAART were  becoming more clear, written in the wasted faces and growing bellies of so many  patients. An increasing number of those who had chosen to start therapy when  the swing swung toward 500 decided to go on extended drug holidays. I treated  many of these patients who did well off medications, some maintaining low viral  loads and improved CD4 counts for several years. This was the one instance that  I can recall when the so-called swing actually swung back down.

Many  providers who had been willing to treat people with higher CD4 counts were  uncomfortable going back to waiting until 200. It was also clear that if one  waited to initiate the conversation on starting until patients hit 200, by the  time adherence and access issues were addressed, therapy was often not  initiated until well below 200. So, many of us started talking about therapy  with patients who had between 300 and 400 T-cells and were starting them on  meds a little earlier. Observational studies at the time seemed to indicate  that treatment appeared to improve outcomes in this range, but there was little  evidence that it was having a big clinical impact above a count of 500.

Data  swings toward 500

In  2008, the first presentations were given of the NA-ACCORD trial, a huge  retrospective review of some of the largest cohorts in the U.S. and Canada. The  results were striking. There was a 70% decrease in all-cause mortality in  patients who initiated therapy with a count between 350 and 500. A later  analysis showed a 60% decrease in mortality in those who started at a count of  500 compared to those who waited until fewer than 500. This was  paradigm-shattering as it really indicated clinical consequences to waiting to  initiate therapy.

There are limitations to retrospective observational  studies. It is possible that those who started therapy earlier could be  longer-lived for reasons having nothing to do with when they started.  Retrospective studies also tend to smooth over some big variations. As I mentioned  earlier, in the late 1990s and early 2000s, there were large numbers of people  who started therapy early but then stopped for extended periods. This was not  accounted for and those people were considered throughout as “early starters.”

In  any case, data from other retrospective studies has supported the observations  in NA-ACCORD. The ART Cohort Collaboration looked at the data a bit differently  and there was a clear benefit up to a count of 400 CD4/mm3 but not  above. A growing consensus emerged and in the 2009 U.S. Department of Health  and Human Services (DHHS) guidelines, it was recommended that therapy should be  initiated in all patients below 350 CD4/mm3 and that therapy should  be considered between 350 and 500 CD4/mm3, especially in pregnant  women and people who were symptomatic, including those with cancers.

By the time the guidelines were rewritten for 2010, many  on the panel felt that the accumulated data was really showing a benefit to  initiating treatment at 500. Less than 350 still had the most hard data behind  it, but there was increasingly more observational data to show decreases in  some of the secondary illnesses being observed as people lived longer with  HIV—things like cardiovascular disease and cancer.

Treatment  reduces transmission

I have to admit that I was skeptical. Starting in 2008,  there was increasing evidence that treating HIV-positive people decreased viral  transmission in the population. There was increasing discussion of inflammatory  markers and the role that inflammation might play in HIV. The idea was also  expressed that everyone was going to need drugs in a few years anyway, so why  not move it up? I didn’t buy it. I failed to see clear-cut evidence of benefit  over 500 CD4s and I did not see how to convince individual patients that there  were benefits for them in the idea that lowering their viral loads served the  public good. Many drugs still had significant side effects, we had seen the  difficulties when patients developed resistance and had few options, and the  last time we pushed the starting line higher it had not been a good idea. This  was a very uncomfortable place for me to be—it was the first time I had ever  found myself thinking more conservatively than the guidelines panel. I wondered  if I had been at this too long.

Over  the last couple of years the lines of thinking mentioned above have become more  firmly established and the evidence for them continues to grow. Rates of HIV  infection in the U.S. have continued at the same levels for almost two decades  now. In my own practice, I have seen so many young men become positive in the  past two years. We have seen high rates of STDs for years, but much of it  seemed to be coming from oral sex. In the last two years, I have seen more anal  gonorrhea and Chlamydia than I remember seeing in a long time. Some men are  looking for any excuse to stop using condoms, the most effective method we have  of preventing transmission for people having sex (although pre-exposure  prophylaxis, PrEP, adds another tool). It has become very clear that our  prevention messages are failing to help people maintain changes in behavior  that would lower transmission rates. For young people today, the horrors of the  AIDS epidemic are just things they learn about in history books, and the fear  of HIV doesn’t last beyond the next hook-up. The right wing in the U.S. has  destroyed sex education in many places and the level of ignorance about STDs is  appalling.

The  CDC and other public health authorities have undertaken a powerful campaign for  treatment as prevention. I think it becomes increasingly clear that reducing  viral load across communities by treating as many people as possible may be our  only real chance of bringing this epidemic under control. So government is  clearly moving to support universal treatment, thus guaranteeing coverage and  access, removing another obstacle on the “con” side of the argument.

As  a primary care provider however, one has to be able to convince the patient  that the therapy being offered is of benefit to him or her. For those in a  relationship with someone of the opposite serostatus, treatment as prevention  does serve the interest of increasing the chance that the negative partner will  stay uninfected. But the reality is that we are experiencing a new kind of  apartheid based on viral load status. Over and over I hear from patients that  they are questioned by potential partners about their viral load. If they are  on meds and undetectable, they are acceptable sex partners. If they are not on  meds, they get rejected. This has pushed some to start therapy earlier.

Trending  toward STRs

For  real personal benefits to be seen, however, powerful trends needed to come into  play. First has been the development of truly tolerable and easy-to-take  medication regimens. We have had Atripla for quite a few years now and its  once-daily dosing made it easy. But many people still experienced side effects.  The development of more once-daily regimens, of two more once-daily fixed dose  combinations, the approval of several twice-daily, well tolerated meds in new  classes—all of these have suddenly presented us with more options, not just for  initial therapy but for sequential regimens as well. And we expect to see a  number of new once-daily and fixed dose combinations in new formulations—PIs  and entry inhibitors without nucleosides, new integrase inhibitors with next  generation nukes, and many others. This is truly the first time in fighting HIV  that, as a provider, I can say to a patient that he or she will most likely not  have any side effects from the medication I’m prescribing.

Inflammation

The  third area of growing consensus has been in regard to the importance of  inflammation as a cause of disease. This is a trend across the entire field of  medicine. Inflammation appears to play important roles in aging, in the  development of cardiovascular disease, in neurologic disease, as well as in  rheumatology, endocrinology, and virtually every other area. People with HIV at  every CD4 count have shown elevated levels of inflammation and immune activation,  as well as heightened risk for a myriad of diseases from blood clots to early  heart attacks. By the time of the International AIDS Conference in Washington,  D.C. last year, the evidence for the deleterious effects of inflammation and  the positive impact of ART on markers of immune activation was becoming  overwhelming. Data continues to accumulate rapidly. As I wrote this article,  two new studies appeared in the New England Journal of  Medicine which showed significant benefit for patients started on  medications very early in the disease process.

The  2012 guidelines gave a stronger recommendation than previously to treating all  patients with fewer than 500 CD4/mm3. There also appeared to be a  growing consensus of expert opinion leading to more universal treatment.

Jumping  off

For  me, the meeting in D.C. brought a kind of epiphany. It finally seemed that the  scales had shifted. The things on the negative side of the scale—the side  effects, complicated regimens, drug access issues, and lack of documented benefit—seemed  to be lightening if not absent. And the side of the scale in favor of treatment  was becoming heavier and heavier with reasons to start early. In fact, it  appears to me that it is time to jump off of the swing at the highest point of  its arc, to stop using CD4 count as a parameter in deciding when to start, and  to offer treatment to all patients who are infected with HIV. I have begun to  do this with overwhelming acceptance by many of my patients. Hopefully, we’ll  land on our feet.