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Are there people cured of HIV by means of HAART?

Are there people cured of HIV by means of HAART?


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I wonder if there people who were cured of HIV only by means of highly active anti retro-viral therapy (HAART) or other drugs rather than by bone marrow transplant?

I know that HAART can suppress HIV below detectable level but are there people who stopped HAART and did not experience the HIV levels rising?


This very recent (and freely available) review pretty much sums the problem up in the introduction:

http://dx.doi.org/10.1038/clpt.2012.202 (Barton et al., 2013: Prospects for Treatment of Latent HIV)

And here's an update more specifically on the problems with actually curing an individual of HIV infection, if you have access: http://dx.doi.org/10.1016/S0140-6736(13)60104-X (Katlama et al., 2013: Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs)

Essentially, current antiretroviral therapy (ART) is able to nearly fully suppress active HIV, practically restoring the individual to a healthy status, including the prevention of transmission from them. However, the therapy needs full adherence (missing a dose can already cause viral loads to rise) and is lifelong. The reason for this is because HIV integrates into the genome of host CD4+ T cells, of which there are latent populations in places difficult to reach with therapeutics such as peripheral lymph nodes.

Apparently, some rare individuals actually achieve a "functional cure", i.e. the body is able to suppress viral replication for a given period of time (5 years) without ART. But these patients "are characterised by a favourable HLA profile and potent HIV-specific CD8 T-cell responses that are associated with a low viral DNA reservoir" (Katlama et al). They also mention another group of five patients who did not seem to have a favourable genetic profile and were still able to control HIV following cessation of ART for several years (http://dx.doi.org/10.1097/QAD.0b013e32833b61ba Hocqueloux, 2010: Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection). So it seems there are plenty reports of people who are able to remain free of detectable viral loads and maintain CD4+ T cell counts for a long time after treatment, but it doesn't seem like any of them stay permanently virus-free.


Since early March we know, that there is the first patient which has been cured by HAART. According to the paper it has been proven that the infant was infected with HIV. This was done by detecting the virus even after the first 48 hours, this rules out that the virus transmitted by the mother without infection.

The infant was first treated when it was 30 hours of age with a triple therapy (zidovudin, lamivudin and nevirapin). On the seventh day the therapy was changed to zidovudin, lamivudin and lopinavir/ritonavir. After one month of therapy no replicable virus particle could be found. The therapy was continued until the age of 18 months. The infant is now 26 months without a sign of a rebound of the HIV infection.

The approach was atypical, since they used a therapy scheme with not established high dosing of the antiretroviral drugs. They ruled out a innate HIV-immunity by certain HLA variants, since Mother and child had matching HLA-Haplotypes. But other genetic mutations are still possbile.

This is scientific progress, the answer to your questions changes in only 2 months.

[1] http://www.retroconference.org/2013b/Abstracts/47897.htm


While it's difficult to prove a negative, I know of no cases where a patient has been treated with HAART to the extent that their viral load never rises again. Keep in mind that, if nothing else, such a study would be extremely hard to do, as proving you've "cured" someone would require extremely long term followup.

HAART is however quite good at suppressing HIV, and there's currently no known upper bound on the lifespan of an HIV+ individual undergoing treatment. Compared to a 10 year post-infection life expectancy a decade or two ago, that's pretty darn good.


How HAART (Highly Active Antiretroviral Therapy) Works

Latesha Elopre, MD, is a board-certified internist specializing in HIV. She is an assistant professor of infectious diseases at the University of Alabama at Birmingham.

HAART is the acronym for "highly active antiretroviral therapy," a term coined in the late 1990s to describe the effectiveness of combination drug therapies used to treat HIV. The term is less commonly used today given that modern antiretrovirals are more than just "highly active" but able to afford people with HIV near-normal life expectancy and prolonged, disease-free health.  

Even so, HAART remains a seminal turning point in the HIV pandemic and the foundation on which modern antiretroviral therapies are built.


'Heavy drinking' means HAART works less well in HIV-positive drug users

HIV-positive patients who are heavy alcohol drinkers respond less well to HAART, according to a study conducted amongst HIV-infected drug users in Miami, published in the March 2003 edition of the journal Addiction Biology. A similar study in HIV-positive men and women with a history of alcohol problems, published in the May edition of Alcoholism: Clinical and Experimental Biology, also found that `at-risk` alcohol users on HAART had higher viral load and lower CD4 cell counts.

There are conflicting data about the role of alcohol in HIV disease progression. Although some investigations have found no link between disease progression and response to HAART between drinkers and non-drinkers, a recent study suggested that heavy alcohol consumption could stimulate latent HIV into replication. In addition, it is thought that heavy drinking can contribute to poor nutrition and this can suppress the immune system. Heavy drinking could negatively affect adherence to HAART as well as damaging the liver’s ability to process antiretrovirals.

To help clarify the role of alcohol in HIV disease progression and the effect of HAART, investigators in Miami looked at the impact of different levels of alcohol consumption on the CD4 cell count, HIV viral load and nutritional status of 220 HIV-positive drug users.

Glossary

The worsening of a disease.

The body's mechanisms for fighting infections and eradicating dysfunctional cells.

Clear, non-cellular portion of the blood, containing antibodies and other proteins and chemicals.

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1 the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret.

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

The average age of patients was 40 years. The majority (70%) were African Americans, and the dominant drug used by patients was crack cocaine (63%), with 46% using cocaine, and 60% cannabis.

A little under two thirds (63%) of patients were categorised as heavy drinkers (defined as drinking alcohol three to four times a week), 21% drank once a week or less and were classed as light drinkers and 16% reported no alcohol use. Men were three times more likely to be heavy drinkers than women.

When investigators looked at the impact of alcohol on nutrition, they found that heavy drinkers were more likely to be malnourished, with 66% having low serum albumin levels, compared to 22% of light drinkers and 16% of non-drinkers. Serum albumin has been found to be an independent predictor of HIV disease progression (see links below).

The average CD4 cell count of heavy drinkers was slightly lower than light users and non-drinkers (381 cells/mm 3 versus 399 cells/mm 3 and 425 cells/mm 3 . However, when the investigators looked at the immunological status of the 63% of patients taking HAART, they found that heavy alcohol users on were twice as likely to have a CD4 cell count below 500 cells/mm 3 compared to light or non -drinkers.

Average viral load amongst the study samples was just over 58,000 copies/mL, with 24% of patients being undetectable. Moreover, only 14% of heavy drinkers had an undetectable viral load compared to 24% of light users, and univariate analysis revealed that HAART-treated patients who drank heavily were four times less likely to achieve an undetectable viral load (95% CI 1, 2-17, p=0.04), compared to light and non-drinkers.

The investigators note that heavy drinkers had poorer immunological function and viral response to therapy. They suggest that several factors could be responsible, including poor drug absorption, interactions, and adherence. They note that alcohol is metabolised by the same cytochrome p450 pathway responsible for the metabolising of protease inhibitors and NNRTIs. They conclude that heavy alcohol use could “block the effectiveness” of HAART and stress the importance of evaluating patterns of drug use.

The second study, carried out by Boston University and Pittsburgh School of Medicine, found that amongst 349 HIV-positive individuals with a history of alcohol abuse, `at risk` drinkers on HAART had higher viral load and lower CD4 counts than those who consumed moderate amounts of alcohol, or none at all. The same relationship was not apparent amongst HIV-positive people not receiving HAART.

Dr Amy Justice of Pittsburgh University said: "Future studies need to determine the degree to which this association is explained by patient behaviour, such as non-adherence, and the degree to which it appears to be a direct effect of alcohol on the immune system of individuals infected with HIV."


What happened to ‘the baby cured of HIV’? Part Two

Of course, SciBlogs is in the middle of a Wordpress update when this news breaks:

Some of you might remember last year, when there was exciting news about a baby, born with HIV, who had subsequently become HIV- thanks to an alternative treatment strategy (basically, give babby HAART ASAP).

The end of last year, the physicians associated with the babby finally published some of their observations.

This led to a rush of 'Me too!' physicians, either trying the same approach, or reporting on their previous HAART attempts. Theres nothing wrong with that at all. One baby should not change the standard of care for babies born to HIV+ mothers. It needs to be replicated in many other environments.

Well, the Canadians had been using this 'aggressive' approach for treating babies for a while, and found it was not the miraculous cure the physicians associated with the first baby had hoped-- The 'miracle' fails 58% of the time.

But these physicians were just *sure* they had cured these kids. which lead to a disturbing trend.

It is considered medically unethical to stop the baby’s drugs now , but Dr. Deveikis and Dr. Yvonne J. Bryson, a pediatric AIDS expert at the University of California, Los Angeles, who is also working on the case, said they would consider stopping them briefly to see what happens if the baby is still virus-free at age 2 .

.

Then chance intervened. One of the children, a now 3-year-old being treated at CHEO, was having difficulty sticking with the medication. Swallowing several tablespoons of unpleasant-tasting medicine twice a day is a common challenge for HIV-positive children.

“Sometimes it’s just not possible to keep going with the medication and because we would rather them not take it at all than take it intermittently, we sometimes, together with the family, make a decision to stop for a while,” said Lindy Samson, an infectious disease physician at CHEO.

Until we figure out how to make sure the kids are cured and not just 'cured', YOU CANT TAKE THE KIDS OFF THE MEDS UNLESS THE MEDS ARE LITERALLY KILLING THEM. If the meds are LITERALLY shredding the kids kidneys/liver/whatever, by all means, take them off the drugs and pray they remain negative.

But in the absence of imminent death. DONT TAKE THEM OFF THE DAMN MEDS!

I CANT BELIEVE I HAVE TO TYPE THAT.

Well, HIV does what we know HIV does. The aggressive HAART didnt happen soon enough to prevent latency (HIV infects a cell and hides). Some of those latent cells reactivated, and now the miracle baby 'cured of HIV' in Mississippi is HIV+ again, because she was never cured of HIV.

And thats all the details I know now, because once again, we are talking about a press release, and not an actual publication.

This is 2014 and physicians are dinging around with kids lives, outside of a proper scientific context.

I was pissed enough at the physician who played games with the lives of two adults. But I have zero patience for this crap in children. I will say this once:

Keep the kids on the fucking drugs, you fucking idiot physicians.


A Jab for HIV?

“A lot of people ask me: When are we going to get an HIV vaccine? And I tell them well we already have them, they’re just not that great,” McNamara explains. “I think that we’ve been spoiled rotten with these COVID vaccines that are 90 to 95 percent effective … they almost raise the bar on immunology as a whole.”

Researchers have been searching for an HIV vaccine for decades . The main barrier has been finding one with a high enough effectiveness rate for pharmaceutical companies to want to invest, and the FDA to approve. Right now, a lot of vaccine trials turn up with something like 40 percent effectiveness, McNamara says. That just doesn’t cut it.

In addition to antibody therapies, McNamara says he’s most excited about the way the field is progressing now that stigmatization of HIV infection has gone down.

“It seems like trust has been built up between the HIV-AIDS community and the medical community. And this took a long time,” McNamara says. “In the early days of the HIV epidemic in the early 1980s, it was ugly. It was really ugly. And it took a lot of effort by a lot of people — including Anthony Fauci — to rectify a lot of those wrongs.” He says that new sense of communication and trust is something he looks forward to. “If you don’t have trust, then you can’t do clinical trials. You can’t implement any new drug regimens.”

As for how close we are to a cure for HIV? “If you were to have asked me that 10 years ago, I might have said never ,” says McNamara. “But I’ve changed my view in the last 10 years. I do actually think we’ll see a cure within my lifetime.”

How broadly and quickly we can deploy that cure is another question — having a cure, or having a vaccine, is different from implementing it worldwide. Edward Jenner discovered the smallpox vaccine in 1796, the last smallpox outbreak in the U.S. was in 1949 , and the disease was declared globally eradicated in 1980. Jonas Salk developed the polio vaccine in 1952, there have been no cases in the U.S. since 1979, but the disease is not quite eradicated globally . How fast will HIV disappear once we have a vaccine?

“I don’t think we’ll eradicate HIV in my lifetime,” says McNamara. “But I would imagine that even by the end of the decade we might have reproducible results where we cure some patients. Doing it on a consistent basis? Probably another 10 years. I think the technology is there.”


Doctor who cured ‘Berlin patient’ of HIV: ‘We knew we were doing something very special’

Dr. Gero Hϋtter, left, with Timothy Ray Brown. After Brown's cure became public, Hϋtter said he received emails daily from people with HIV saying "Please doctor, do the same for me." Photo by Robert Hood / Fred Hutch News Service

When Dr. Gero Hütter gave Timothy Ray Brown a bone marrow transplant at a Berlin hospital on Feb. 7, 2007, he knew he could be making history. If, that is, Brown survived long enough to see whether the grueling transplant cured not only his leukemia but also his infection with HIV, the virus that causes AIDS.

Brown did survive, and eight years later, is free of both cancer and HIV. On Thursday, the German doctor reunited with his Seattle-born patient for a rare joint public appearance to talk about how the world’s first -- and so far only -- HIV cure came about and what it means for the future.

“At the time we were doing the transplant, we knew we were doing something very special that could change the whole medical world if it worked,” Hütter told a standing-room-only crowd of more than 200 people - including Brown’s mother – at the downtown Seattle Public Library. “We weren’t clear what would happen. It was a big and good surprise that it worked.”

Added Brown: “I didn’t really believe I was cured until he published the paper [in the New England Journal of Medicine in 2009].”

Identified only as “the Berlin patient” in that first paper and in subsequent media reports, Brown, 48, went public in 2010, around the time he returned from Berlin to live in the United States.

“I decided I needed to tell my story so other people could get cured as well,” he said. “I decided I was going to be an activist for a cure for HIV.”

At Thursday’s talk and during a visit earlier in the day to Fred Hutchinson Cancer Research Center – which pioneered bone marrow transplants and is now home to a research consortium on curing HIV – Hütter talked about what it was like to be the doctor who brought about the cure.

The idea

An oncologist by training, Hütter, 45, is the first to admit that he didn’t know much about HIV. But like many doctors who came of age or trained in the 1980s or early 1990s – before antiretroviral therapy revolutionized AIDS treatment, for those who have access to and can tolerate the drugs – he was deeply affected by the epidemic.

“I was very scared of HIV when it came out in the ‘80s,” he said. “It was my time when my sexual activity started. I was scared of this thing. When I started medical school in 1992, there was no active treatment, and I saw people die.”

That was why a paper he read while in medical school made such an impression on him. It described a rare genetic mutation called the CCR5 delta-32 deletion, which confers natural resistance to HIV. The mutation prevents CD4 cells – infection-fighting white blood cells that HIV targets – from developing a receptor, called a CCR5, on their surfaces. HIV uses this receptor to enter the cell. Without it, it’s as though HIV is left standing at the door without a key to get in.

“I was so impressed as a student that I kept this information for 10 years in my mind,” Hütter said. “When Timothy came and I saw he had leukemia and HIV, it was clear to me that we had to find a donor who had this mutation.”

Guinea pig

For his part, Brown wasn’t interested in “being a guinea pig,” he said. He was far more concerned about his new diagnosis – acute myeloid leukemia – than his old one. He had learned in 1995 that he was infected with HIV, but a year later, antiretroviral therapy was found to control it. So he hoped to be able to cure his cancer with chemotherapy rather than a riskier transplant. But when chemotherapy failed, he agreed to Hütter’s plan to try to cure both.

The transplant itself was no different from what any patient with leukemia would undergo except that it required an additional step beyond the already complex process of finding a tissue-type match between donor and patient: A matching donor also had to have two copies of the CCR5 mutation, one from each parent.

It helped that Germany, where Brown was living at the time, had a large, centralized registry of stem cell donors, and the CCR5 mutation is most common in northern Europeans. Testing for the mutation is fairly simple and cost only an additional $500, Hütter said. Brown had a high number of tissue-type matches – 232. The 61 st one tested had both copies of the mutation.

Hütter turned to data from Fred Hutch, amassed from years of transplant research, to assure himself that stem cells with the mutation would not adversely affect the leukemia treatment. (On Thursday – his first actual visit to the Seattle campus – he said, “For a hematologist, the Hutch is the Holy Grail.”)

As is typical for a stem cell transplant, Brown underwent “conditioning,” an intense chemotherapy and radiation regimen that destroys the immune system to make room for transplanted immune cells to grow. On the day of the transplant – in a ward of the Berlin hospital named after a patient treated at Fred Hutch – he stopped taking his antiretroviral medication.

“The key reason I believed it would work is because [Hütter] was so certain it would work,” Brown said.

‘At the right place at the right time’

Hütter did not sugar-coat the rigors of the transplant itself. Nor did he outright promise an HIV cure, as hopeful as his plan seemed.

“It made sense that it would work,” he said. But there were risks, beyond the transplant itself. For one thing, sensitive tests done before the transplant had found that in addition to the strain of HIV that uses the CCR5 receptor to enter cells, Brown harbored traces of a rarer strain that uses a different receptor. Even if the transplant prevented infection by the more common strain, it was possible that the other strain would emerge to re-infect him.

“That would be a bad situation,” Hütter said. “But you can treat it [with antiretrovirals].”

In addition, medicine, Hütter pointed out, “is not always 100 percent. There will be patients for whom these procedures don’t work.”

In fact, in the years since Brown’s treatment, efforts to replicate his cure have failed to show the same results, mostly because the patients died from the cancer or the transplant before it could be determined whether their HIV was gone. In one case, the rarer strain emerged. That has not happened with Brown.

Although ever the scientist, Hütter acknowledges the role that chance – or luck if you have it – played in Brown’s cure. “He was at the right place at the right time,” Hütter said, undergoing treatment with an oncologist who remembered the 10-year-old HIV paper in a city with a good stem cell registry and access to a population with the needed mutation.

But he also points out the role that Brown played in his own treatment.

“What I admire about Timothy is his motivation,” he said. “You can’t cure cancer just with motivation. But when he came to us, he organized his life. The food was bad in the hospital, so he brought in his own food. He did workouts. Some patients lie in the bed and say, ‘Doctor, come cure me.’ He understood that he had to do his part. That’s unusual. We had a good doctor-patient relationship.”

The motivation was needed especially when Brown’s leukemia – though not his HIV – returned a year later, and he needed a second transplant. Recovery from that one was much more difficult, leaving him needing to learn to walk and talk all over again.

While Hütter and Brown are very different on the outside – one a married, mild-mannered scientist-physician, the other a gay activist who once modeled himself after Boy George – they share a straightforward manner of speaking, a dry sense of humor and a professed lack of emotionalism that can belie their continued close relationship.

“We don’t exchange Christmas cards,” cracked Brown.

“I miss always his birthday,” said Hütter.

The two men also share a passion in doing what they can to push for a cure for HIV that is easier, less risky and less expensive than what Brown endured and which everyone agrees is appropriate only for someone who needs a transplant primarily to cure cancer.

‘Please doctor, do the same for me’

As an oncologist, Hütter was so unknown in the HIV field and a cure was considered so unlikely that it took almost a year after he first reported the results of Brown’s transplant for a medical journal to publish his paper.

What Hütter revealed Thursday night was the immediate – and overwhelming – reaction to the case by people with HIV.

“After the case become public, I received nearly every day emails, requests from people with HIV. ‘Please doctor, do the same for me, I give you any money.’” Hütter said. “I tried to answer every one. Sometimes it was my main work in a day to answer these questions.”

Today, others are working hard on finding answers for patients desperate for a cure. Some, including the Hutch-based defeatHIV consortium, are using Brown’s case as a blueprint for cure work centering on gene modification.

Led by virologist Dr. Keith Jerome and stem cell and gene therapy specialist Dr. Hans-Peter Kiem, the plan is to take an HIV-infected person’s own stem cells and knock out or disable the gene that acts as the HIV doorway, mimicking the genetics of someone who has natural resistance. The modified cells would then be returned to the patient.

Two other federally funded consortiums are investigating different approaches, and Hütter believes a cure will likely involve a mix, including a way to wipe out a reservoir of HIV that lies dormant in the body, hiding from antiretroviral therapy but roaring back if therapy is discontinued.

The overwhelming need for a cure was evident from the number of people who lined up Thursday evening to ask questions of Hütter and Brown. Perhaps the most poignant came from Moses Nsubuga, a member of the International Network for Strategic Initiatives in Global HIV Trials, who was visiting Seattle from Uganda.

“You are a symbol of hope in this struggle,” he said to Hütter and Brown. “I come from a continent where you have 70 percent of the people living with HIV. People are hopeless. These days, they hear so much about Timothy Brown. When I go back to Africa, one of them will ask me, ‘Is there a possibility of bringing Timothy to Africa so that he can interact with millions of people living with HIV?’”

“I definitely want to do that,” Brown said. “I want to help.”

Mary Engel is a former staff writer at Fred Hutchinson Cancer Research Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.


When HIV multiplies, many of the new copies have mutations: they are slightly different from the original virus. Some mutant viruses keep multiplying even when you are taking an ARV drugs. When this happens, the virus can develop resistance to the drug and ART may stop working. See Fact Sheet 126 for more information.

If only one or two ARV drugs are used, it is easy for the virus to develop resistance. For this reason, using just one or two drugs is not recommended. But if two or three drugs are used, a successful mutant would have to "get around" all of the drugs at the same time. Using combination therapy means that it takes much longer for resistance to develop.


The Take-Home About HIV Treatment

Whether you are newly diagnosed with HIV, a long-term survivor, or anyone in between, it’s never too late to embrace the advancements in treatment knowledge that will help you live a long, productive, and pleasurable life—physically, emotionally, and sexually.

Here are some take-home points to carry with you as you journey forward:

  1. Get on antiretroviral therapy (ART).
  2. Take care of your mental health.
  3. Alternative therapies can be helpful, but do your research.
  4. Demand the medical care you deserve—you are worth it!
  5. Tailor your treatment so it fits your life.

HIV treatment is a comprehensive plan, not just a daily pill. Talk about it with people you trust, find out what’s available to you, use the options you feel are best for you, and give yourself permission to live your best life.


Contents

There are six classes of drugs, which are usually used in combination, to treat HIV infection. Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. Typical combinations include two nucleoside reverse-transcriptase inhibitors (NRTI) as a "backbone" along with one non-nucleoside reverse-transcriptase inhibitor (NNRTI), protease inhibitor (PI) or integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) as a "base." [6]

Chloroquine, a zinc ionophore, shows antiviral activity against HIV and reduction of immune activation. [9] [10] [11] [12]

Entry inhibitors Edit

Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Maraviroc and enfuvirtide are the two available agents in this class. Maraviroc works by targeting CCR5, a co-receptor located on human helper T-cells. Caution should be used when administering this drug, however, due to a possible shift in tropism which allows HIV to target an alternative co-receptor such as CXCR4. [ citation needed ]

In rare cases, individuals may have a mutation in the CCR5 delta gene which results in a nonfunctional CCR5 co-receptor and in turn, a means of resistance or slow progression of the disease. However, as mentioned previously, this can be overcome if an HIV variant that targets CXCR4 becomes dominant. [13] To prevent fusion of the virus with the host membrane, enfuvirtide can be used. Enfuvirtide is a peptide drug that must be injected and acts by interacting with the N-terminal heptad repeat of gp41 of HIV to form an inactive hetero six-helix bundle, therefore preventing infection of host cells. [14]

Nucleoside/nucleotide reverse-transcriptase inhibitors Edit

Nucleoside reverse-transcriptase inhibitors (NRTI) and nucleotide reverse-transcriptase inhibitors (NtRTI) are nucleoside and nucleotide analogues which inhibit reverse transcription. HIV is an RNA virus, so it can not be integrated into the DNA in the nucleus of the human cell unless it is first "reverse" transcribed into DNA. Since the conversion of RNA to DNA is not naturally done in the mammalian cell, it is performed by a viral protein, reverse transcriptase, which makes it a selective target for inhibition. NRTIs are chain terminators. Once NRTIs are incorporated into the DNA chain, their lack of a 3' OH group prevents the subsequent incorporation of other nucleosides. Both NRTIs and NtRTIs act as competitive substrate inhibitors. Examples of NRTIs include zidovudine, abacavir, lamivudine, emtricitabine, and of NtRTIs – tenofovir and adefovir. [15]

Non-nucleoside reverse-transcriptase inhibitors Edit

Non-nucleoside reverse-transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an allosteric site of the enzyme NNRTIs act as non-competitive inhibitors of reverse transcriptase. NNRTIs affect the handling of substrate (nucleotides) by reverse transcriptase by binding near the active site. NNRTIs can be further classified into 1st generation and 2nd generation NNRTIs. 1st generation NNRTIs include nevirapine and efavirenz. 2nd generation NNRTIs are etravirine and rilpivirine. [15] HIV-2 is naturally resistant to NNRTIs. [16]

Integrase inhibitors Edit

Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the viral enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors under clinical trial, [ when? ] and raltegravir became the first to receive FDA approval in October 2007. Raltegravir has two metal binding groups that compete for substrate with two Mg 2+ ions at the metal binding site of integrase. As of early 2014, two other clinically approved integrase inhibitors are elvitegravir and dolutegravir. [17]

Protease inhibitors Edit

Protease inhibitors block the viral protease enzyme necessary to produce mature virions upon budding from the host membrane. Particularly, these drugs prevent the cleavage of gag and gag/pol precursor proteins. [18] Virus particles produced in the presence of protease inhibitors are defective and mostly non-infectious. Examples of HIV protease inhibitors are lopinavir, indinavir, nelfinavir, amprenavir and ritonavir. Darunavir and atazanavir are recommended as first line therapy choices. [6] Maturation inhibitors have a similar effect by binding to gag, but development of two experimental drugs in this class, bevirimat and vivecon, was halted in 2010. [19] Resistance to some protease inhibitors is high. Second generation drugs have been developed that are effective against otherwise resistant HIV variants. [18]

The life cycle of HIV can be as short as about 1.5 days from viral entry into a cell, through replication, assembly, and release of additional viruses, to infection of other cells. [20] HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse transcription. Its short life-cycle and high error rate cause the virus to mutate very rapidly, resulting in a high genetic variability. Most of the mutations either are inferior to the parent virus (often lacking the ability to reproduce at all) or convey no advantage, but some of them have a natural selection superiority to their parent and can enable them to slip past defenses such as the human immune system and antiretroviral drugs. The more active copies of the virus, the greater the possibility that one resistant to antiretroviral drugs will be made. [21]

When antiretroviral drugs are used improperly, multi-drug resistant strains can become the dominant genotypes very rapidly. In the era before multiple drug classes were available (pre-1997), the reverse-transcriptase inhibitors zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were used serially or in combination leading to the development of multi-drug resistant mutations. [22]

In contrast, antiretroviral combination therapy defends against resistance by creating multiple obstacles to HIV replication. This keeps the number of viral copies low and reduces the possibility of a superior mutation. [21] If a mutation that conveys resistance to one of the drugs arises, the other drugs continue to suppress reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for long these agents must be taken in combinations in order to have a lasting effect. As a result, the standard of care is to use combinations of antiretroviral drugs. [6] Combinations usually consist of three drugs from at least two different classes. [6] This three drug combination is commonly known as a triple cocktail. [23] Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations. [ citation needed ]

Because of HIV's tendency to mutate, when patients who have started an antiretrovial regimen fail to take it regularly, resistance can develop. [24] On the other hand, patients who take their medications regularly can stay on one regimen without developing resistance. [24] This greatly increases life expectancy and leaves more drugs available to the individual should the need arise. [ citation needed ]

In recent years, [ when? ] drug companies have worked together to combine these complex regimens into single-pill fixed-dose combinations. [25] More than 20 antiretroviral fixed-dose combinations have been developed. This greatly increases the ease with which they can be taken, which in turn increases the consistency with which medication is taken (adherence), [26] and thus their effectiveness over the long-term.

Adjunct treatment Edit

Although antiretroviral therapy has helped to improve the quality of life of people living with HIV, there is still a need to explore other ways to further address the disease burden. One such potential strategy that was investigated was to add interleukin 2 as an adjunct to antiretroviral therapy for adults with HIV. A Cochrane review included 25 randomized controlled trials that were conducted across six countries. [27] The researchers found that interleukin 2 increases the CD4 immune cells, but does not make a difference in terms of death and incidence of other infections. Furthermore, there is probably an increase in side-effects with interleukin 2. The findings of this review do not support the use of interleukin 2 as an add-on treatment to antiretroviral therapy for adults with HIV. [ citation needed ]

Initiation of antiretroviral therapy Edit

Antiretroviral drug treatment guidelines have changed over time. Before 1987, no antiretroviral drugs were available and treatment consisted of treating complications from opportunistic infections and malignancies. After antiretroviral medications were introduced, most clinicians agreed that HIV positive patients with low CD4 counts should be treated, but no consensus formed as to whether to treat patients with high CD4 counts. [28]

In April 1995, Merck and the National Institute of Allergy and Infectious Diseases began recruiting patients for a trial examining the effects of a three drug combination of the protease inhibitor indinavir and two nucleoside analogs. [29] illustrating the substantial benefit of combining 2 NRTIs with a new class of anti-retrovirals, protease inhibitors, namely indinavir. Later that year David Ho became an advocate of this "hit hard, hit early" approach with aggressive treatment with multiple antiretrovirals early in the course of the infection. [30] Later reviews in the late 90s and early 2000s noted that this approach of "hit hard, hit early" ran significant risks of increasing side effects and development of multidrug resistance, and this approach was largely abandoned. The only consensus was on treating patients with advanced immunosuppression (CD4 counts less than 350/μL). [31] Treatment with antiretrovirals was expensive at the time, ranging from $10,000 to $15,000 a year. [32]

The timing of when to start therapy has continued to be a core controversy within the medical community, though recent [ when? ] studies have led to more clarity. The NA-ACCORD [33] study observed patients who started antiretroviral therapy either at a CD4 count of less than 500 versus less than 350 and showed that patients who started ART at lower CD4 counts had a 69% increase in the risk of death. [33] In 2015 the START [34] and TEMPRANO [35] studies both showed that patients lived longer if they started antiretrovirals at the time of their diagnosis, rather than waiting for their CD4 counts to drop to a specified level.

Other arguments for starting therapy earlier are that people who start therapy later have been shown to have less recovery of their immune systems, [36] and higher CD4 counts are associated with less cancer. [37]

The European Medicines Agency (EMA) has recommended the granting of marketing authorizations for two new antiretroviral (ARV) medicines, rilpivirine (Rekambys) and cabotegravir (Vocabria), to be used together for the treatment of people with human immunodeficiency virus type 1 (HIV-1) infection. [38] The two medicines are the first ARVs that come in a long-acting injectable formulation. [38] This means that instead of daily pills, people receive intramuscular injections monthly or every two months. [38]

The combination of Rekambys and Vocabria injection is intended for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current ARV treatment, and when the virus has not developed resistance to certain class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INIs). [38]

Treatment as prevention Edit

A separate argument for starting antiretroviral therapy that has gained more prominence is its effect on HIV transmission. ART reduces the amount of virus in the blood and genital secretions. [39] [40] This has been shown to lead to dramatically reduced transmission of HIV when one partner with a suppressed viral load (<50 copies/ml) has sex with a partner who is HIV negative. In clinical trial HPTN 052, 1763 serodiscordant heterosexual couples in 9 countries were planned to be followed for at least 10 years, with both groups receiving education on preventing HIV transmission and condoms, but only one group getting ART. The study was stopped early (after 1.7 years) for ethical reasons when it became clear that antiviral treatment provided significant protection. Of the 28 couples where cross-infection had occurred, all but one had taken place in the control group consistent with a 96% reduction in risk of transmission while on ART. The single transmission in the experimental group occurred early after starting ART before viral load was likely to be suppressed. [41] Pre-Exposure Prophylaxis (PrEP) provides HIV-negative individuals with medication—in conjunction with safer-sex education and regular HIV/STI screenings—in order to reduce the risk of acquiring HIV. [42] In 2011, the journal Science gave the Breakthrough of the Year award to treatment as prevention. [43]

In July 2016 a consensus document was created by the Prevention Access Campaign which has been endorsed by over 400 organisations in 58 countries. The consensus document states that the risk of HIV transmission from a person living with HIV who has been undetectable for a minimum of 6 months is negligible to non-existent, with negligible being defined as 'so small or unimportant to be not worth considering'. The Chair of the British HIV Association (BHIVA), Chloe Orkin, stated in July 2017 that 'there should be no doubt about the clear and simple message that a person with sustained, undetectable levels of HIV virus in their blood cannot transmit HIV to their sexual partners.' [44]

Furthermore, the PARTNER study, [45] which ran from 2010–2014, enrolled 1166 serodiscordant couples (where one partner is HIV positive and the other is negative) in a study that found that the estimated rate of transmission through any condomless sex with the HIV-positive partner taking ART with an HIV load less than 200 copies/mL was zero. [45]

In summary, as the WHO HIV treatment guidelines state, "The ARV regimens now available, even in the poorest countries, are safer, simpler, more effective and more affordable than ever before." [46]

There is a consensus among experts that, once initiated, antiretroviral therapy should never be stopped. This is because the selection pressure of incomplete suppression of viral replication in the presence of drug therapy causes the more drug sensitive strains to be selectively inhibited. This allows the drug resistant strains to become dominant. This in turn makes it harder to treat the infected individual as well as anyone else they infect. [6] One trial showed higher rates of opportunistic infections, cancers, heart attacks and death in patients who periodically interrupted their ART. [47] [48]

Guideline sources Edit

There are several treatment guidelines for HIV-1 infected adults in the developed world (that is, those countries with access to all or most therapies and laboratory tests). In the United States there are both the International AIDS Society-USA (IAS-USA) (a 501(c)(3) not-for-profit organization in the USA) [49] as well as the US government's Department of Health and Human Services guidelines. [6] In Europe there are the European AIDS Clinical Society guidelines. [50]

For resource limited countries, most national guidelines closely follow the World Health Organization guidelines. [5]

Guidelines Edit

The guidelines use new criteria to consider starting HAART, as described below. However, there remain a range of views on this subject and the decision of whether to commence treatment ultimately rests with the patient and his or her doctor. [ citation needed ]

The US DHHS guidelines (published April 8, 2015) state:

  • Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression.
  • ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.
  • Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence. Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.

The newest World Health Organization guidelines (dated September 30, 2015) now agree and state: [5]

  • Antiretroviral therapy (ART) should be initiated in everyone living with HIV at any CD4 cell count

Baseline resistance Edit

Baseline resistance is the presence of resistance mutations in patients who have never been treated before for HIV. In countries with a high rate of baseline resistance, resistance testing is recommended before starting treatment or, if the initiation of treatment is urgent, then a "best guess" treatment regimen should be started, which is then modified on the basis of resistance testing. [16] In the UK, there is 11.8% medium to high-level resistance at baseline to the combination of efavirenz + zidovudine + lamivudine, and 6.4% medium to high level resistance to stavudine + lamivudine + nevirapine. [51] In the US, 10.8% of one cohort of patients who had never been on ART before had at least one resistance mutation in 2005. [52] Various surveys in different parts of the world have shown increasing or stable rates of baseline resistance as the era of effective HIV therapy continues. [53] [54] [55] [56] With baseline resistance testing, a combination of antiretrovirals that are likely to be effective can be customized for each patient. [ citation needed ]

Regimens Edit

Most HAART regimens consist of three drugs: 2 NRTIs ("backbone")+ a PI/NNRTI/INSTI ("base"). Initial regimens use "first-line" drugs with a high efficacy and low side-effect profile.

The US DHHS preferred initial regimens for adults and adolescents in the United States, as of April 2015, are: [6]

  • tenofovir/emtricitabine and raltegravir (an integrase inhibitor)
  • tenofovir/emtricitabine and dolutegravir (an integrase inhibitor) /lamivudine (two NRTIs) and dolutegravir for patients who have been tested negative for the HLA-B*5701 gene allele
  • tenofovir/emtricitabine, elvitegravir (an integrase inhibitor) and cobicistat (inhibiting metabolism of the former) in patients with good kidney function (gfr > 70)
  • tenofovir/emtricitabine, ritonavir, and darunavir (both latter are protease inhibitors)

Both efavirenz and nevirapine showed similar benefits when combined with NRTI respectively. [57]

In the case of the protease inhibitor based regimens, ritonavir is used at low doses to inhibit cytochrome p450 enzymes and "boost" the levels of other protease inhibitors, rather than for its direct antiviral effect. This boosting effect allows them to be taken less frequently throughout the day. [58] Cobicistat is used with elvitegravir for a similar effect but does not have any direct antiviral effect itself. [59]

The WHO preferred initial regimen for adults and adolescents as of June 30, 2013 is: [46]

Special populations Edit

Acute infection Edit

In the first six months after infection HIV viral loads tend to be elevated and people are more often symptomatic than in later latent phases of HIV disease. There may be special benefits to starting antiretroviral therapy early during this acute phase, including lowering the viral "set-point" or baseline viral load, reduce the mutation rate of the virus, and reduce the size of the viral reservoir (See section below on viral reservoirs). [6] The SPARTAC trial compared 48 weeks of ART vs 12 weeks vs no treatment in acute HIV infection and found that 48 weeks of treatment delayed the time to decline in CD4 count below 350 cells per ml by 65 weeks and kept viral loads significantly lower even after treatment was stopped. [60]

Since viral loads are usually very high during acute infection, this period carries an estimated 26 times higher risk of transmission. [61] By treating acutely infected patients, it is presumed that it could have a significant impact on decreasing overall HIV transmission rates since lower viral loads are associated with lower risk of transmission (See section on treatment as prevention). However an overall benefit has not been proven and has to be balanced with the risks of HIV treatment. Therapy during acute infection carries a grade BII recommendation from the US DHHS. [6]

Children Edit

HIV can be especially harmful to infants and children, with one study in Africa showing that 52% of untreated children born with HIV had died by age 2. [62] By five years old, the risk of disease and death from HIV starts to approach that of young adults. The WHO recommends treating all children less than 5 years old, and starting all children older than 5 with stage 3 or 4 disease or CD4 <500 cells/ml. [46] DHHS guidelines are more complicated but recommend starting all children less than 12 months old and children of any age who have symptoms. [63]

As for which antiretrovirals to use, this is complicated by the fact that many children who are born to mothers with HIV are given a single dose of nevirapine (an NNRTI) at the time of birth to prevent transmission. If this fails it can lead to NNRTI resistance. [64] Also, a large study in Africa and India found that a PI based regimen was superior to an NNRTI based regimen in children less than 3 years who had never been exposed to NNRTIs in the past. [65] Thus the WHO recommends PI based regimens for children less than 3.

The WHO recommends for children less than 3 years: [46]

and for children 3 years to less than 10 years and adolescents <35 kilograms:

US DHHS guidelines are similar but include PI based options for children > 3 years old. [63]

A systematic review assessed the effects and safety of abacavir-containing regimens as first-line therapy for children between 1 month and 18 years of age when compared to regimens with other NRTIs. [66] This review included two trials and two observational studies with almost eleven thousand HIV infected children and adolescents. They measured virologic suppression, death and adverse events. The authors found that there is no meaningful difference between abacavir-containing regimens and other NRTI-containing regimens. The evidence is of low to moderate quality and therefore it is likely that future research may change these findings. [ citation needed ]

Pregnant women Edit

The goals of treatment for pregnant women include the same benefits to the mother as in other infected adults as well as prevention of transmission to her child. The risk of transmission from mother to child is proportional to the plasma viral load of the mother. Untreated mothers with a viral load >100,000 copies/ml have a transmission risk of over 50%. [67] The risk when viral loads are < 1000 copies/ml are less than 1%. [68] ART for mothers both before and during delivery and to mothers and infants after delivery are recommended to substantially reduce the risk of transmission. [69] The mode of delivery is also important, with a planned Caesarian section having a lower risk than vaginal delivery or emergency Caesarian section. [68]

HIV can also be detected in breast milk of infected mothers and transmitted through breast feeding. [70] The WHO balances the low risk of transmission through breast feeding from women who are on ART with the benefits of breastfeeding against diarrhea, pneumonia and malnutrition. It also strongly recommends that breastfeeding infants receive prophylactic ART. [46] In the US, the DHHS recommends against women with HIV breastfeeding. [69]

Older adults Edit

With improvements in HIV therapy, several studies now estimate that patients on treatment in high-income countries can expect a normal life expectancy. [71] [72] This means that a higher proportion of people living with HIV are now older and research is ongoing into the unique aspects of HIV infection in the older adult. There is data that older people with HIV have a blunted CD4 response to therapy but are more likely to achieve undetectable viral levels. [73] However, not all studies have seen a difference in response to therapy. [74] The guidelines do not have separate treatment recommendations for older adults, but it is important to take into account that older patients are more likely to be on multiple non-HIV medications and consider drug interactions with any potential HIV medications. [75] There are also increased rates of HIV associated non-AIDS conditions (HANA) such as heart disease, liver disease and dementia that are multifactorial complications from HIV, associated behaviors, coinfections like hepatitis B, hepatitis C, and human papilloma virus (HPV) as well as HIV treatment. [75]

Adults with depression Edit

Many factors may contribute to depression in adults living with HIV, such as the effects of the virus on the brain, other infections or tumours, antiretroviral drugs and other medical treatment. [76] Rates of major depression are higher in people living with HIV compared to the general population, and this may negatively influence antiretroviral treatment. In a systematic review, Cochrane researchers assessed whether giving antidepressants to adults living with both HIV and depression may improve depression. [76] Ten trials, of which eight were done in high-income countries, with 709 participants were included. Results indicated that antidepressants may be better in improving depression compared to placebo, but the quality of the evidence is low and future research is likely to impact on the findings. [ citation needed ]

There are several concerns about antiretroviral regimens that should be addressed before initiating:

  • Intolerance: The drugs can have serious side-effects which can lead to harm as well as keep patients from taking their medications regularly.
  • Resistance: Not taking medication consistently can lead to low blood levels that foster drug resistance. [77]
  • Cost: The WHO maintains a database of world ART costs [78] which have dropped dramatically in recent [when?] years as more first line drugs have gone off-patent. [79] A one pill, once a day combination therapy has been introduced in South Africa for as little as $10 per patient per month. [80] One recent [when?] study estimated an overall cost savings to ART therapy in South Africa given reduced transmission. [81] In the United States, new on-patent regimens can cost up to $28,500 per patient, per year. [82][83]
  • Public health: Individuals who fail to use antiretrovirals as directed can develop multi-drug resistant strains which can be passed onto others. [84]

Virologic response Edit

Suppressing the viral load to undetectable levels (<50 copies per ml) is the primary goal of ART. [58] This should happen by 24 weeks after starting combination therapy. [85] Viral load monitoring is the most important predictor of response to treatment with ART. [86] Lack of viral load suppression on ART is termed virologic failure. Levels higher than 200 copies per ml is considered virologic failure, and should prompt further testing for potential viral resistance. [6]

Research has shown that people with an undetectable viral load are unable to transmit the virus through condomless sex with a partner of either gender. The 'Swiss Statement' of 2008 described the chance of transmission as 'very low' or 'negligible,' [87] but multiple studies have since shown that this mode of sexual transmission is impossible where the HIV-positive person has a consistently undetectable viral load. This discovery has led to the formation of the Prevention Access Campaign are their 'U=U' or 'Undetectable=Untransmittable' public information strategy, [88] [89] an approach that has gained widespread support amongst HIV/AIDS-related medical, charitable, and research organisations. [44] The studies demonstrating that U=U is an effective strategy for preventing HIV transmission in serodiscordant couples so long as "the partner living with HIV [has] a durably suppressed viral load" include: [90] Opposites Attract, [91] PARTNER 1, [45] PARTNER 2, [92] [93] (for male-male couples) [90] and HPTN052 [94] (for heterosexual couples). [90] In these studies, couples where one partner was HIV-positive and one partner was HIV-negative were enrolled and regular HIV testing completed. In total from the four studies, 4097 couples were enrolled over four continents and 151,880 acts of condomless sex were reported, there were zero phylogenetically linked transmissions of HIV where the positive partner had an undetectable viral load. [95] Following this the U=U consensus statement advocating the use of 'zero risk' was signed by hundreds of individuals and organisations including the US CDC, British HIV Association and The Lancet medical journal. [44] The importance of the final results of the PARTNER 2 study were described by the medical director of the Terrence Higgins Trust as "impossible to overstate," while lead author Alison Rodger declared that the message that "undetectable viral load makes HIV untransmittable . can help end the HIV pandemic by preventing HIV transmission." [96] The authors summarised their findings in The Lancet as follows: [92]

Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV. [92]

This result is consistent with the conclusion presented by Anthony S. Fauci, the Director of the National Institute of Allergy and Infectious Diseases for the U.S. National Institutes of Health, and his team in a viewpoint published in the Journal of the American Medical Association, that U=U is an effective HIV prevention method when an undetectable viral load is maintained. [2] [90]

Immunologic response Edit

CD4 cell counts are another key measure of immune status and ART effectiveness. [85] CD4 counts should rise 50 to 100 cells per ml in the first year of therapy. [58] There can be substantial fluctuation in CD4 counts of up to 25% based on the time of day or concomitant infections. [97] In one long-term study, the majority of increase in CD4 cell counts was in the first two years after starting ART with little increase afterwards. This study also found that patients who began ART at lower CD4 counts continued to have lower CD4 counts than those who started at higher CD4 counts. [98] When viral suppression on ART is achieved but without a corresponding increase in CD4 counts it can be termed immunologic nonresponse or immunologic failure. While this is predictive of worse outcomes, there is no consensus on how to adjust therapy to immunologic failure and whether switching therapy is beneficial. DHHS guidelines do not recommend switching an otherwise suppressive regimen. [6] [99]

Innate lymphoid cells (ILC) are another class of immune cell that is depleted during HIV infection. However, if ART is initiated before this depletion at around 7 days post infection, ILC levels can be maintained. While CD4 cell counts typically replenish after effective ART, ILCs depletion is irreversible with ART initiated after the depletion despite suppression of viremia. [100] Since one of the roles of ILCs is to regulate the immune response to commensal bacteria and to maintain an effective gut barrier, [101] it has been hypothesized that the irreversible depletion of ILCs plays a role in the weakened gut barrier of HIV patients, even after successful ART. [102]

In patients who have persistently detectable viral loads while taking ART, tests can be done to investigate whether there is drug resistance. Most commonly a genotype is sequenced which can be compared with databases of other HIV viral genotypes and resistance profiles to predict response to therapy. [103] Resistance testing may improve virological outcomes in those who have treatment failures. However, there is lack of evidence of effectiveness of such testing in those who have not done any treatment before. [104]

If there is extensive resistance a phenotypic test of a patient's virus against a range of drug concentrations can be performed, but is expensive and can take several weeks, so genotypes are generally preferred. [6] Using information from a genotype or phenotype, a regimen of 3 drugs from at least 2 classes is constructed that will have the highest probability of suppressing the virus. If a regimen cannot be constructed from recommended first line agents it is termed salvage therapy, and when 6 or more drugs are needed it is termed mega-HAART. [105]

Drug holidays (or "structured treatment interruptions") are intentional discontinuations of antiretroviral drug treatment. As mentioned above, randomized controlled studies of structured treatment interruptions have shown higher rates of opportunistic infections, cancers, heart attacks and death in patients who took drug holidays. [47] [48] [106] With the exception of post exposure prophylaxis, treatment guidelines do not call for the interruption of drug therapy once it has been initiated. [6] [46] [85] [106]

Each class and individual antiretroviral carries unique risks of adverse side effects.

NRTIs Edit

The NRTIs can interfere with mitochondrial DNA synthesis and lead to high levels of lactate and lactic acidosis, liver steatosis, peripheral neuropathy, myopathy and lipoatrophy. [58] First-line NRTIs such as lamivudine/emtrictabine, tenofovir, and abacavir are less likely to cause mitochondrial dysfunction. [107] [108]

Mitochondrial Haplogroups(mtDNA), non pathologic mutations inherited from the maternal line, have been linked to the efficacy of CD4+ count following ART. [109] [110] [111] [112] Idiosyncratic toxicity with mtDNA haplogroup is also well studied.(Boeisteril et al, 2007). [113]

NNRTIs Edit

NNRTIs are generally safe and well tolerated. The main reason for discontinuation of efavirenz is neuro-psychiatric effects including suicidal ideation. Nevirapine can cause severe hepatotoxicity, especially in women with high CD4 counts. [114]

Protease inhibitors Edit

Protease inhibitors (PIs) are often given with ritonavir, a strong inhibitor of cytochrome P450 enzymes, leading to numerous drug-drug interactions. They are also associated with lipodystrophy, elevated triglycerides and elevated risk of heart attack. [115]

Integrase inhibitors Edit

Integrase inhibitors (INSTIs) are among the best tolerated of the antiretrovirals with excellent short and medium term outcomes. Given their relatively new development there is less long term safety data. They are associated with an increase in creatinine kinase levels and rarely myopathy. [116]

When people are exposed to HIV-positive infectious bodily fluids either through skin puncture, contact with mucous membranes or contact with damaged skin, they are at risk for acquiring HIV. Pooled estimates give a risk of transmission with puncture exposures of 0.3% [117] and mucous membrane exposures 0.63%. [118] United States guidelines state that "feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they are visibly bloody." [119] Given the rare nature of these events, rigorous study of the protective abilities of antiretrovirals are limited but do suggest that taking antiretrovirals afterwards can prevent transmission. [120] It is unknown if three medications are better than two. The sooner after exposure that ART is started the better, but after what period they become ineffective is unknown, with the US Public Health Service Guidelines recommending starting prophylaxis up to a week after exposure. [119] They also recommend treating for a duration of four weeks based on animal studies. Their recommended regimen is emtricitabine + tenofovir + raltegravir (an INSTI). The rationale for this regimen is that it is "tolerable, potent, and conveniently administered, and it has been associated with minimal drug interactions." [119] People who are exposed to HIV should have follow up HIV testing at six, 12, and 24 weeks. [ citation needed ]

Women with HIV have been shown to have decreased fertility which can affect available reproductive options. [121] In cases where the woman is HIV negative and the man is HIV positive, the primary assisted reproductive method used to prevent HIV transmission is sperm washing followed by intrauterine insemination (IUI) or in vitro fertilization (IVF). Preferably this is done after the man has achieved an undetectable plasma viral load. [122] In the past there have been cases of HIV transmission to an HIV-negative partner through processed artificial insemination, [123] but a large modern series in which followed 741 couples where the man had a stable viral load and semen samples were tested for HIV-1, there were no cases of HIV transmission. [124]

For cases where the woman is HIV positive and the man is HIV negative, the usual method is artificial insemination. [122] With appropriate treatment the risk of mother-to-child infection can be reduced to below 1%. [125]

Several buyers clubs sprang up since 1986 to combat HIV. AZT nucleoside reverse-transcriptase inhibitor (NRTI), zidovudine (AZT) was not effective on its own. It was approved by the US FDA in 1987. [126] The FDA bypassed stages of its review for safety and effectiveness in order to distribute this drug earlier. [127] Subsequently, several more NRTIs were developed but even in combination were unable to suppress the virus for long periods of time and patients still inevitably died. [128] To distinguish from this early antiretroviral therapy (ART), the term highly active antiretroviral therapy (HAART) was introduced. In 1996 by sequential publications in The New England Journal of Medicine by Hammer and colleagues [129] and Gulick and colleagues [29] illustrating the substantial benefit of combining 2 NRTIs with a new class of antiretrovirals, protease inhibitors, namely indinavir. This concept of 3-drug therapy was quickly incorporated into clinical practice and rapidly showed impressive benefit with a 60% to 80% decline in rates of AIDS, death, and hospitalization. [1]

As HAART became widespread, fixed dose combinations were made available to ease the administration. Later, the term combination antiretroviral therapy (cART) gained favor with some physicians as a more accurate name, not conveying to patients any misguided idea of the nature of the therapy. [130] Today multidrug, highly effective regimens are long since the default in ART, which is why they are increasingly called simply ART instead of HAART or cART. [130] This retronymic process is linguistically comparable to the way that the words electronic computer and digital computer at first were needed to make useful distinctions in computing technology, but with the later irrelevance of the distinction, computer alone now covers their meaning. Thus as "all computers are digital now", so "all ART is combination ART now." However, the names HAART and cART, reinforced by thousands of earlier mentions in medical literature still being regularly cited, also remain in use. [ citation needed ]

People living with HIV can expect to live a nearly normal life span if able to achieve durable viral suppression on combination antiretroviral therapy. However this requires lifelong medication and will still have higher rates of cardiovascular, kidney, liver and neurologic disease. [131] This has prompted further research towards a cure for HIV.

Patients cured of HIV infection Edit

The so-called "Berlin patient" has been potentially cured of HIV infection and has been off of treatment since 2006 with no detectable virus. [132] This was achieved through two bone marrow transplants that replaced his immune system with a donor's that did not have the CCR5 cell surface receptor, which is needed for some variants of HIV to enter a cell. [133] Bone marrow transplants carry their own significant risks including potential death and was only attempted because it was necessary to treat a blood cancer he had. Attempts to replicate this have not been successful and given the risks, expense and rarity of CCR5 negative donors, bone marrow transplant is not seen as a mainstream option. [131] It has inspired research into other methods to try to block CCR5 expression through gene therapy. A procedure zinc-finger nuclease-based gene knockout has been used in a Phase I trial of 12 humans and led to an increase in CD4 count and decrease in their viral load while off antiretroviral treatment. [134] Attempt to reproduce this failed in 2016. Analysis of the failure showed that gene therapy only successfully treats 11-28% of cells, leaving the majority of CD4+ cells capable of being infected. The analysis found that only patients where less than 40% of cells were infected had reduced viral load. The Gene therapy was not effective if the native CD4+ cells remained. This is the main limitation which must be overcome for this treatment to become effective. [135]

After the "Berlin patient", two additional patients with both HIV infection and cancer were reported to have no traceable HIV virus after successful stem cell transplants. Virologist Annemarie Wensing of the University Medical Center Utrecht announced this development during her presentation at the 2016 "Towards an HIV Cure" symposium. [136] [137] [138] However, these two patients are still on antiretroviral therapy, which is not the case for the Berlin patient. Therefore, it is not known whether or not the two patients are cured of HIV infection. The cure might be confirmed if the therapy were to be stopped and no viral rebound occurred. [139]

In March 2019, a second patient, referred to as the "London Patient", was confirmed to be in complete remission of HIV. Like the Berlin Patient, the London Patient received a bone marrow transplant from a donor who has the same CCR5 mutation. He has been off antiviral drugs since September 2017, indicating the Berlin Patient was not a "one-off". [140] [141]

Viral reservoirs Edit

The main obstacle to complete elimination of HIV infection by conventional antiretroviral therapy is that HIV is able to integrate itself into the DNA of host cells and rest in a latent state, while antiretrovirals only attack actively replicating HIV. The cells in which HIV lies dormant are called the viral reservoir, and one of the main sources is thought to be central memory and transitional memory CD4+ T cells. [142] In 2014 there were reports of the cure of HIV in two infants, [143] presumably due to the fact that treatment was initiated within hours of infection, preventing HIV from establishing a deep reservoir. [144] There is work being done [ when? ] to try to activate reservoir cells into replication so that the virus is forced out of latency and can be attacked by antiretrovirals and the host immune system. Targets include histone deacetylase (HDAC) which represses transcription and if inhibited can lead to increased cell activation. The HDAC inhibitors valproic acid and vorinostat have been used in human trials with only preliminary results so far. [145] [146]

Immune activation Edit

Even with all latent virus deactivated, it is thought that a vigorous immune response will need to be induced to clear all the remaining infected cells. [131] Strategies include using cytokines to restore CD4+ cell counts as well as therapeutic vaccines to prime immune responses. [147] One such candidate vaccine is Tat Oyi, developed by Biosantech. [148] This vaccine is based on the HIV protein tat. Animal models have shown the generation of neutralizing antibodies and lower levels of HIV viremia. [149]

Direct-to-consumer and other advertisements for HIV drugs in the past were criticized for their use of healthy, glamorous models rather than typical people with HIV/AIDS. Usually, these people will present with debilitating conditions or illnesses as a result of HIV/AIDS. In contrast, by featuring people in unrealistically strenuous activities, such as mountain climbing, [150] this proved to be offensive and insensitive to the suffering of people who are HIV positive. The US FDA reprimanded multiple pharmaceutical manufacturers for publishing such adverts in 2001, as the misleading advertisements harmed consumers by implying unproven benefits and failing to disclose important information about the drugs. [151] Overall, some drug companies chose not to present their drugs in a realistic way, which consequently harmed the general public's ideas [ citation needed ] , suggesting that HIV would not affect you as much as suggested. This led to people not wanting to get tested [ citation needed ] , for fear of being HIV positive, because at the time (in the 80s and 90s particularly), having contracted HIV was seen as a death sentence, as there was no known cure. An example of such a case is Freddie Mercury [ citation needed ] , who died in 1991, aged 45, of AIDS-related Pneumonia.

The preamble to the World Health Organization's Constitution defines health as "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity." [152] Those living with HIV today are met with other challenges that go beyond the singular goal of lowering their viral load. A 2009 meta-analysis studying the correlates of HIV-stigma found that individuals living with higher stigma burden were more likely to have poorer physical and mental health. [8] Insufficient social support and delayed diagnosis due to decreased frequency of HIV testing and knowledge of risk reduction were cited as some of the reasons. [8] [153] [7] [154] [155] People living with HIV (PLHIV) have lower health related quality of life (HRQoL) scores than do the general population. [154] [153] The stigma of having HIV is often compounded with the stigma of identifying with the LGBTQ community or the stigma of being an injecting drug user (IDU) even though heterosexual sexual transmission accounts for 85% of all HIV-1 infections worldwide. [156] [106] AIDS has been cited as the most heavily stigmatized medical condition among infectious diseases. [155] Part of the consequence of this stigma toward PLHIV is the belief that they are seen as responsible for their status and less deserving of treatment. [156] [8]

A 2016 study sharing the WHO's definition of health critiques its 90-90-90 target goal, which is part of a larger strategy that aims to eliminate the AIDS epidemic as a public health threat by 2030, by arguing that it does not go far enough in ensuring the holistic health of PLHIV. [7] The study suggests that maintenance of HIV and AIDS should go beyond the suppression of viral load and the prevention of opportunistic infection. It proposes adding a 'fourth 90' addressing a new 'quality of life' target that would focus specifically on increasing the quality of life for those that are able to suppress their viral load to undetectable levels along with new metrics to track the progress toward that target. [7] This study serves as an example of the shifting paradigm in the dynamics of the health care system from being heavily 'disease-oriented' to more 'human-centered'. Though questions remain of what exactly a more 'human-centered' method of treatment looks like in practice, it generally aims to ask what kind of support, other than medical support, PLHIV need to cope with and eliminate HIV-related stigmas. [8] [7] Campaigns and marketing aimed at educating the general public in order to reduce any misplaced fears of HIV contraction is one example. [8] Also encouraged is the capacity-building and guided development of PLHIV into more leadership roles with the goal of having a greater representation of this population in decision making positions. [8] Structural legal intervention has also been proposed, specifically referring to legal interventions to put in place protections against discrimination and improve access to employment opportunities. [8] On the side of the practitioner, greater competence for the experience of people living with HIV is encouraged alongside the promotion of an environment of nonjudgment and confidentiality. [8]

Psychosocial group interventions such as psychotherapy, relaxation, group support, and education may have some beneficial effects on depression in HIV positive people. [157]

The successful treatment and management of HIV/AIDS is affected by a plethora of factors which ranges from successfully taking prescribed medications, preventing opportunistic infection, and food access etc. Food insecurity is a condition in which households lack access to adequate food because of limited money or other resources. Food insecurity is a global issue that have affect billions of people yearly including those living in developed countries.

Food insecurity is a major public health disparity in the United States of America, which significantly affects minority groups, people living at or below the poverty line, and those who are living with one or more morbidity. As of December 31, 2017, there were approximately 126,742 people living with HIV/AIDS (PLWHA) in NYC, of which 87.6% can be described as living with some level of poverty and food insecurity as reported by the NYC Department of Health March 31st, 2019. [158] Having access to a consistent food supply that is safe and healthy is an important part in the treatment and management of HIV/AIDS. PLWHA are also greatly affected by food inequities and food deserts which causes them to be food insecure. Food insecurity, which can cause malnutrition, can also negatively impact HIV treatment and recovery from opportunistic infections. Similarly, PLWHA require additional calories and nutritionally support that require foods free from contamination to prevent further immunocompromising. Food insecurity can further exacerbate the progression of HIV/AIDS and can prevent PLWHA from consistently following their prescribed regimen, which will lead to poor outcomes.

It is imperative that these food insecurity among PLWHA are addressed and rectified to reduce this health inequity. [159] [ circular reference ] It is important to recognized that socioeconomic status, access to medical care, geographic location, public policy, race and ethnicity all play a pivotal role in the treatment and management of HIV/AIDS. The lack of sufficient and constant income does limit the options for food, treatment, and medications. The same can be inferred for those who are among the oppressed groups in society who are marginalized and may be less inclined or encouraged to seek care and assistance. Endeavors to address food insecurity should be included in HIV-treatment programs and may help improve health outcomes if it also focuses on health equity among the diagnosed as much as it focuses on medications. Access to consistently safe and nutritious foods is one of the most important facets in ensuring PLWHA are being provided the best possible care. By altering the narratives for HIV treatment so that more support can be garnered to reduce food insecurity and other health disparities mortality rates will decrease for people living with HIV/AIDS.

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What is the treatment for high cholesterol?

Treatment for high cholesterol begins with lifestyle changes. Sometimes cholesterol-lowering medicine is also needed. The most common medicines used to reduce cholesterol levels are called statins.

In people with HIV, treatment for high cholesterol may include changing an HIV regimen to avoid taking HIV medicines that can increase cholesterol levels.

Some HIV medicines can interact with medicines that lower cholesterol levels. Health care providers carefully consider potential drug interactions between HIV medicines and any other medicines a person may be taking.