Cervical Cancer and Human Papilloma Virus Infection

Human papillomavirus (HPV) is the most common viral infection of the reproductive tract. Most sexually active women and men will be infected at some point in their lives and some may be repeatedly infected.

The peak time for acquiring infection for both women and men is shortly after becoming sexually active. HPV is sexually transmitted, but penetrative sex is not required for transmission. Skin-to-skin genital contact is a well-recognized mode of transmission.

There are many types of HPV, and many do not cause problems. HPV infections usually clear up without any intervention within a few months after acquisition, and about 90% clear within 2 years. A small proportion of infections with certain types of HPV can persist and progress to cancer.

Cervical cancer is by far the most common HPV-related disease. Nearly all cases of cervical cancer can be attributable to HPV infection.

Though data on anogenital cancers other than cancer of the cervix are limited, there is an increasing body of evidence linking HPV with cancers of the anus, vulva, vagina, and penis. Although these cancers are less frequent than cancer of the cervix, their association with HPV make them potentially preventable using similar primary prevention strategies as those for cervical cancer.

Non-cancer causing types of HPV (especially types 6 and 11) can cause genital warts and respiratory papillomatosis (a disease in which tumours grow in the air passages leading from the nose and mouth into the lungs). Although these conditions very rarely result in death, they may cause significant occurrence of disease. Genital warts are very common and highly infectious.

Signs and symptoms

The majority of HPV infections do not cause symptoms or disease and resolve spontaneously. However, persistent infection with specific types of HPV (most frequently types 16 and 18) may lead to precancerous lesions. If untreated, these lesions may progress to cervical cancer, but this progression usually takes many years.

Symptoms of cervical cancer tend to appear only after the cancer has reached an advanced stage and may include:

• irregular, intermenstrual (between periods) or abnormal vaginal bleeding after sexual intercourse;
• back, leg or pelvic pain;
• fatigue, weight loss, loss of appetite;
• vaginal discomfort or odourous discharge; and
• a single swollen leg.

More severe symptoms may arise at advanced stages.

How HPV infection leads to cervical cancer

Although most HPV infections clear up on their own and most pre-cancerous lesions resolve spontaneously, there is a risk for all women that HPV infection may become chronic and pre-cancerous lesions progress to invasive cervical cancer.

It takes 15 to 20 years for cervical cancer to develop in women with normal immune systems. It can take only 5 to 10 years in women with weakened immune systems, such as those with untreated HIV infection.

Risk factors for HPV persistence and development of cervical cancer

• Early first sexual intercourse
• Multiple sexual partners
• Tobacco use
• Immune suppression (for example, HIV-infected individuals are at higher risk of HPV infection and are infected by a broader range of HPV types)

Scope of the problem

Worldwide, cervical cancer is the fourth most frequent cancer in women with an estimated 530 000 new cases in 2012 representing 7.5% of all female cancer deaths. Of the estimated more than 270 000 deaths from cervical cancer every year, more than 85% of these occur in less developed regions.

In developed countries, programmes are in place which enable women to get screened, making most pre-cancerous lesions identifiable at stages when they can easily be treated. Early treatment prevents up to 80% of cervical cancers in these countries.

In developing countries, limited access to effective screening means that the disease is often not identified until it is further advanced and symptoms develop. In addition, prospects for treatment of such late-stage disease may be poor, resulting in a higher rate of death from cervical cancer in these countries.

The high mortality rate from cervical cancer globally (52%) could be reduced by effective screening and treatment programmes.

Screening for cervical cancer

Cervical cancer screening is testing for pre-cancer and cancer among women who have no symptoms and may feel perfectly healthy. When screening detects pre-cancerous lesions, these can easily be treated and cancer avoided. Screening can also detect cancer at an early stage and treatment has a high potential for cure.

Because pre-cancerous lesions take many years to develop, screening is recommended for every woman from aged 30 to 49 at least once in a lifetime and ideally more frequently. Screening is only effective on cervical cancer mortality, if a high proportion of women participate.

There are 3 different types of screening tests are currently available:

• conventional (Pap) test and liquid-based cytology (LBC)
• visual inspection with Acetic Acid (VIA)
• HPV testing for high-risk HPV types.

HPV vaccination

There are currently 2 vaccines which protect against both HPV 16 and 18, which are known to cause at least 70% of cervical cancers. The vaccines may also have some cross-protection against other less common HPV types which cause cervical cancer. One of the vaccines also protects against HPV types 6 and 11 which cause anogenital warts.

Clinical trial results show that both vaccines are safe and very effective in preventing infection with HPV 16 and 18.

Both vaccines work best if administered prior to exposure to HPV. Therefore, it is preferable to administer them before first sexual activity.

The vaccines cannot treat HPV infection or HPV-associated disease such as cancer.

Some countries have started to vaccinate boys as the vaccination prevents genital cancers in males as well as females, and one of the two available vaccines also prevents genital warts in males and females. WHO recommends vaccination for girls aged 9-13 years as this is the most cost-effective public health measure against cervical cancer.

HPV vaccination does not replace cervical cancer screening. In countries where HPV vaccine is introduced, screening programmes may still need to be developed or strengthened.

Cervical cancer prevention and control: A comprehensive approach

WHO recommends a comprehensive approach to cervical cancer prevention and control. The recommended set of actions includes interventions across the life course. It should be multidisciplinary, including components from community education, social mobilization, vaccination, screening, treatment and palliative care.

Primary prevention begins with HPV vaccination of girls aged 9-13 years, before they become sexually active.

Other recommended preventive interventions for boys and girls as appropriate are:

• education about safe sexual practices, including delayed start of sexual activity;
• promotion and provision of condoms for those already engaged in sexual activity;
• warnings about tobacco use, which often starts during adolescence, and which is an important risk factor for cervical and other cancers; and
• male circumcision.

Women who are sexually active should be screened for abnormal cervical cells and pre-cancerous lesions, starting from 30 years of age.

Source: http://www.who.int/news-room/fact-sheets/detail/human-papillomavirus-(hpv)-and-cervical-cancer

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Integrase Inhibitors: An Overview

Integrase inhibitors (also known as integrase strand transfer inhibitors, or INSTIs) are a powerful class of antiretroviral drug which prevents HIV from integrating its genetic coding (genome) into the DNA of the infected host cell. It does so by blocking an enzyme called integrase and, by doing so, makes it impossible for HIV to replicate.

As a class of drugs, integrase inhibitors are considered advantageous in treating HIV infection, with easier dosing requirements, lower side effects, improved resistance profiles, and greater durability.

Current guidance from the U.S. Department of Health and Human Services places integrase inhibitors as a preferred, first-line agent for persons newly treated for HIV. In fact, of the six treatment options currently recommended for newly treated patients, five contain an integrase inhibitor as their backbone drug agent.

Mechanism

HIV integrates its viral genome into the host cell's DNA in a five-step process:
The integrase enzyme binds to HIV DNA, the latter of which is created in a process called reverse transcription.

The HIV DNA is then prepared for integration in a process called cleaving, which literally cleaves the viral genetic strand, leaving open gaps in its structure.

The cleaved strand is then inserted into the host cell's nucleus through a nuclear pore.

Once inside the nucleus, the HIV DNA is transferred into the host DNA in is what's called a strand transfer reaction. In this stage, the viral DNA the literally attacks the host cell's DNA, separating the bonds that hold the host DNA together and attaching itself through the chemical gaps in the viral DNA strand.

The attack then incites a natural protective response called gap repair, in which the host cell will automatically repair any damage to the DNA, essentially facilitating the takeover of its genetic coding.

Simply by blocking the integrase enzyme, the entire integration process is stopped, effectively ending the virus' life cycle. However, as integration is only one of several stages of the HIV life cycles, other drugs are taken to inhibit other stages, further preventing HIV from replicating and ensuring that viral activity is fully suppressed (as measured by the HIV viral load).

Side Effects and Considerations

Unlike other classes of HIV drug, integrase inhibitors work directly on the viral mechanisms themselves rather than on cells. As such, they tend have far fewer side effect, primarily diarrhoea, nausea, fatigue, headache, and insomnia.

Most of these side effects, however, are transient and usually resolve on their own. With that being said, if you experience any adverse event while taking an integrase inhibitor drug combination, advise your doctor or clinic immediately. Do not stop treatment without at least speaking to a qualified professional. Stopping and changing prematurely can do more harm than good.

Similarly, while integrase inhibitors are less to prone to premature drug resistance, you should avoid missing doses or gaps in treatment. Resistance occurs when drug levels in the blood begin to fall, allowing mutant viruses to emerge and proliferate. When this happens, your drugs will not be able to work as well as before and may, in some cases, fail.

Since integrase inhibitors remain in the blood stream for longer periods of time, they are able to suppress HIV mutants even when doses are occasionally missed. But it's important to understand that prolonged interruptions are ill advised and that daily adherence remain key to treatment success.

Source: https://www.verywellhealth.com/integrase-inhibitors-48802
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Chlamydia Infection May Pave Way For Cancer via DNA Damage

The bacterium Chlamydia trachomatis is a leading cause of sexually transmitted disease that infects over 90 million people worldwide every year. Chlamydia infection often goes unnoticed, can persist for years with little or no symptoms, and can damage women's reproductive organs.

As well as this, the bacterium is proving increasingly stubborn to shift: antibacterial drugs are often no longer strong enough to eradicate it completely, so it goes into persistent mode, leading to chronic infection with no symptoms.

Chlamydia Uses Various Tactics to Ensure Survival

Chlamydia uses "Trojan horse" tactics to enter host cells unnoticed. A protein called Pgp3 enhances Chlamydia's ability to enter host cells unnoticed and then evade host defences.

To ensure survival, Chlamydia needs to make the most of the resources inside the host cell, which is where the bacterium spends most of its life. Once inside the host cell, the pathogen goes about changing the cell to make itself at home. It re-arranges host cell processes to favour its own growth and proliferation. But it's not clear how this affects the cell's normal functions and whether it leads to disease.

However, there is evidence that it might: there is a growing mountain of epidemiological data linking Chlamydia infections to the development of cervical and ovarian cancer development. But exactly how this might come about has been somewhat of a mystery - until now.

Chlamydia Causes Lasting Genetic Damage to Host Cells

In this new study, the researchers show that Chlamydia makes a long-lasting impression on the genome and epi-genome of host cells. Such changes are increasingly implicated in the development of a range of cancers.

They found host cells acutely and persistently infected with Chlamydia had increased levels of different kinds of DNA breaks.

In normal cells, when these types of breaks occur, they either go into cell suicide mode (apoptosis, where the cell is removed, broken down and its material parts recycled) or DNA repair mode.

In DNA repair mode, special proteins trigger a process called DNA Damage Response which attempts to reseal the broken strands of DNA to make sure the correct sequence of genetic code is restored (so when the cell replicates it produces healthy daughter cells).

But not only did the researchers find that Chlamydia-infected cells had altered DNA, but also that their DNA Damage Response didn't work properly: so the broken DNA didn't get repaired in those cells that didn't go down the cell suicide route.

Chlamydia disrupted the host cell DNA Damage Response by stopping key proteins from reaching the sites of DNA damage.

Chlamydia Damage to Cells Is Similar to that Which Leads to Cancer

Thus Chlamydia-infected, damaged cells that did not go down the cell suicide route continued to proliferate, passing on the DNA damage, and also spurred by some extra pro-survival signals activated in the host cell by the pathogen.

The result is an increasing population of rogue host cells that have escaped the normal mechanisms that ensure faulty DNA is not replicated: a hallmark of cancer.

The discovery is important because if it is established that an infection leads to cancer, then vaccination to prevent the infection, or antibiotics to eliminate it, may also prevent the cancer.

Such preventive methods are already working with other cancer-causing agents such as Human Papilloma Virus (HPV) and Helicobacter pylori, which can cause cervical and gastric cancer, respectively.

However, the path from infection to cancer needs to be firmly established before such a strategy can be considered in the case of Chlamydia.

Source: https://www.medicalnewstoday.com/articles/262350.php

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Monthly Once: HIV Drugs on the Horizon

One of the main barriers to HIV drug success is the high level of adherence needed to attain the clinical goals of therapy. For some, the daily task of taking antiretroviral drugs can be overwhelming, particularly when accompanied by emotional or functional issues that can adversely impact the lives—and adherence—of people with living HIV. 

So profound are these issues that, in the U.S. today, more than 20% of people on antiretroviral therapy are able to maintain an undetectable viral load, the measure for treatment success.

In response, scientists have now begun to explore long-acting drugs, as well as drug delivery systems, that may eventually allow for once-monthly—or even once-quarterly—dosing, either to treat HIV infection or to prevent it.

Long-Lasting Investigational Drugs

In 2013, two long-acting antiretroviral agents were introduced at the 7th annual International AIDS Society (IAS) Conference in Kuala Lumpur. The investigational drugs were both developed as injectable nanosuspensions, wherein tiny crystals of active drug are suspended in liquid, allowing for the slow and steady release of the medication into the system.

The first, cabotegravir (also known as GSK1265744) belongs to a class of drugs called integrase inhibitors, which blocks an enzyme called integrase that HIV needs to multiply. The second, TMC278-LA, is a long-acting formulation of the drug Edurant (ripilvirine) currently used in HIV therapy.

A number of Phase II clinical trials have shown the cabotegravir delivered intramuscularly is generally well tolerated with a mean half-life of between 21 to 50 days (compared to 40 hours following a single, oral dose). Similar studies demonstrated that the drug also ensured sustained drug concentration in rectal and vaginal tissues, suggesting that it could be administered as an effective, long-acting means of pre-exposure prophylaxis (PrEP).

By comparison, a Phase I study showed that TMC278-LA was able to maintain target plasma drug concentrations from 12-26 weeks. The drug also demonstrated promise as PrEP, with stronger concentrations seen in rectal tissues when compared to vaginal tissues.

On-going investigations are planned with the goal of expanding research to Phase II and III clinical trials.

Subdermal Antiretroviral Implants

Scientists at the Oak Crest Institute of Science in Pasadena, California reported developing a matchstick-sized implant that could deliver steady concentrations of antiretroviral medications when implanted beneath the skin.

Similar in design to long-acting contraceptive implants, the device was shown in early research to be able to deliver controlled, sustained release of the drug tenofovir alafenamide (TAF) for up to 40 days.

While research is currently focusing on the device for PrEP, it is suggested that other long-acting agents could eventually be used to provide combination antiretroviral therapy (cART) to people living with HIV.

Future research hopes to open the door to the development of implants that can last for up to a year or more.

Source: https://www.verywellhealth.com/once-monthly-hiv-drugs-on-the-horizon-49311

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Latent HIV Reservoir

A latent HIV reservoir is a group of immune cells in the body that are infected with HIV but are not actively producing new HIV.

HIV attacks immune system cells in the body and uses the cells’ machinery to make copies of itself. After entering the body, HIV inserts its genetic blueprint into the DNA of an immune system cell, such as a CD4 cell. The infected cell starts producing HIV proteins that act as the building blocks for new HIV. To find out more about how HIV attacks cells, read the AIDSinfo HIV Life Cycle fact sheet.

Some HIV-infected cells, however, go into a resting (or latent) state. While in this resting state, the infected cells don’t produce new HIV.

When HIV infects cells in this way, it can hide out inside these cells for years, forming a latent HIV reservoir. At any time, cells in the latent reservoir can become active again and start making more HIV.

Latent HIV reservoirs can be found throughout the body, including in the brain, lymph nodes, blood, and digestive tract.

HIV medicines reduce the amount of HIV in the body (called the viral load) by preventing the virus from multiplying. Because the HIV-infected cells in a latent reservoir aren’t producing new copies of the virus, HIV medicines have no effect on them.

People with HIV must take a daily combination of HIV medicines (called an HIV regimen) to keep their viral loads low. If someone is not taking HIV medicines when the infected cells of the latent reservoir begin making HIV again, the viral load in the body will start to increase. That’s why it’s important to continue taking HIV medicines every day as prescribed, even when viral load levels are low.

Finding ways to target and destroy latent reservoirs is one of the major challenges facing HIV researchers. New studies are exploring different strategies for clearing out reservoirs, including:

·         Using gene therapy (which means manipulating genes to treat or prevent disease) to cut out certain HIV genes and inactivate the virus in HIV-infected immune cells.

·         Developing drugs or other methods that reactivate latent HIV reservoirs so that the immune system or new therapies can effectively eliminate them.

·         Developing approaches that enhance the immune system’s ability to recognize and clear reactivated latent HIV reservoirs.

Source: https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/93/what-is-a-latent-hiv-reservoir-

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