Dosing

Pregnancy

Tenofovir/emtricitabine has been studied in several trials that involved pregnant women. The limited data available indicate that the regimen is safe and does not lead to any adverse outcomes in the newborn. However, the priority is always non-drug therapy to reduce the risk of HIV infection in pregnant women. Even though current short-term data indicate that the pre-exposure chemoprophylaxis with tenofovir/emtricitabine is safe in pregnancy, all patients should be cautioned about the possibility of adverse outcomes. Tenofovir/emtricitabine is known to pass into breast milk.

Adverse Effects

Overall, tenofovir/emtricitabine is well tolerated by most individuals. However, some people may experience the following adverse effects:

• Headache
• Nausea
• Abdominal pain
• Diarrhea
• Weight loss

Rare, Serious Adverse Effects

• Rarely the drug combination may cause liver dysfunction and lactic acidosis. 
• In patients with hepatitis B, there can be worsening of the infection. Consequently, these patients should be closely monitored with regular liver function studies.
• When the drug combination is used for more than 3 to 6 months, some individuals may start to develop bone thinning, and thus some healthcare workers choose to obtain a baseline bone scan. A diet rich in calcium and dairy products is highly recommended in any patient with bone thinning prior to the start of therapy.
• Mild fat redistribution and reaccumulation may be seen in some individuals, and this is often associated with weight loss.

Potential for Drug Interactions

Tenofovir is known to interact with other antiretroviral drugs. When coadministered with these agents, the following may occur:

• When tenofovir is coadministered with didanosine, it increases the serum concentrations of the latter, and this can lead to complications like peripheral neuropathy and pancreatitis. Thus, the dose of didanosine has to be reduced or discontinued in patients taking tenofovir.
• When tenofovir is coadministered with atazanavir, it can decrease the serum concentrations of the latter but increases concentrations of tenofovir. Thus, one must monitor the patient for tenofovir toxicity.
• When tenofovir is co-administered with lopinavir/ritonavir, it can lead to tenofovir toxicity.
• Tenofovir/emtricitabine also can interact adversely with other agents like adefovir, lamivudine, dabigatran, and vincristine.

Recent studies show that patients taking tenofovir/emtricitabine should not combine it with high doses of non-steroidal anti-inflammatory drugs, as this can lead to new onset or worsening of renal impairment.

What is the cost of tenofovir/emtricitabine?

In the United States, the retail cost for a 30-day supply of this drug combination varies from $1400 to $1600. In Canada, the cost is anywhere from $800 to $1200, and unlike in the United States, most insurers do not cover the cost. Outside of North America, the cost per pill has been subsidized in Asia and Africa and varies from $0.20 to $0.40, which averages to about $8 to $15 a month, still a large sum in poverty-stricken areas of Africa and Asia.

Financial Support

Several programs make tenofovir/emtricitabine more affordable by offering assistance with medication costs, co-payments, and insurance. However, patients should search out the best possible options because irrespective of what insurance is selected, the annual cost of this combination drug is expensive. The company that manufactures tenofovir/emtricitabine does have several programs for individuals who are unable to buy the product. Most US insurers cover the cost of tenofovir/emtricitabine, but the co-payments are very high. For those without insurance, some medication-assistance programs make the drug combination available for free. Outside of North America and Europe, the cost of tenofovir/emtricitabine is prohibitively expensive, and most people cannot afford it.[3][7][9]

 A history of HIV exposure followed by diagnostic confirmation.

Screening for human immunodeficiency virus infection is important because infected individuals may remain asymptomatic for years. Serologic tests evaluate for HIV infection. [10][11]The following secondary testing may be performed to assist with diagnosis or staging:

• Lymph node biopsy
• Proviral DNA polymerase chain reaction (PCR)
• Genotyping of viral DNA/RNA
• Viral culture

Approved Drugs

At the moment, the only antiretroviral combination approved for pre-exposure chemoprophylaxis is tenofovir/emtricitabine. Tenofovir not only has a long half-life, but it also is safe, relatively inexpensive, and can be found in high concentrations in macrophages, monocytes, and genital secretions. The few clinical trials that have taken place have involved tenofovir with or without emtricitabine. The combination of tenofovir/emtricitabine was approved several years ago for pre-exposure chemoprophylaxis against HIV in men who have sex with men, as well as for heterosexually-active, serodiscordant men and women.[6][7][8]

Another agent that could potentially be used in pre-exposure chemoprophylaxis is maraviroc. The drug is classified as a CCR5 co-receptor antagonist. It is known to achieve high concentrations in rectal and genital secretions. Plans are to study the drug in future clinical trials.

Pre-Exposure Chemoprophylaxis Pilot Programs

To ensure that pre-exposure chemoprophylaxis is safe and effective many pilot programs have been conducted both in the United States and abroad. It is one of the first pilot programs implemented in San Francisco in 2012. Over the past five years, data indicates high adherence and no new HIV infections among the individuals who have participated. The San Francisco program also has a website that sends reminders about the importance of medication adherence to new clients.

Another program with high success is one in Brazil that has focused on men who have sex with men and transgender women. In 2011, only 22% of men who have sex with men had heard about the program, but over the next four years participation grew to 60%, and it is anticipated that it will reach 95% in the next 12 months. Unlike other countries, Brazil is offering free, pre-exposure chemoprophylaxis to those who cannot afford it (WHO, 2015).

Other similar programs have taken place Zimbabwe, Kenya, Uganda, and South Africa. A key feature of the African program is offering legal advice and informing sex workers of their basic human rights. The limited data available indicate that the programs seem to be working and not many new cases of HIV are being reported in the individuals who have participated (WHO, 2015).

Concerns with Pre-Exposure Chemoprophylaxis

While there are many advantages to using pre-exposure chemoprophylaxis to prevent HIV in high-risk patients, experts state that the following points need to be kept in mind:

• It may lead to changes in sexual behavior. Because such a treatment is available, more people may again develop liberal, sexual habits like those in the pre-HIV era and stop using condoms or engage in high-risk sexual activities
• There is a concern that drug resistance may become a major issue and widespread use of antiretroviral drugs could get out of control
• Burkitt lymphoma 
• Candidiasis
• Coccidiodomycosis and valley fever
• Cryptococcosis
• Cryptosporidiosis
• Cytomegalovirus
• Hepes simplex virus
• High grade malignant immunoblastic lymphoma
• MAC
• Toxoplasmosis
• Some individuals have high genetic resistance to tenofovir, and thus the treatment may not work
• Cost is a significant issue and may be a deterrent for many high-risk individuals

Monitoring After Initiation Pre-Exposure Chemoprophylaxis

When an individual is prescribed tenofovir/emtricitabine as part of pre-exposure chemoprophylaxis, healthcare workers should do the following:

• Because this drug combination is not 100% effective in preventing HIV, the patient must be educated on changes in lifestyle to prevent the acquisition of HIV
• Perform an HIV test to make sure that the individual is HIV-negative before initiating tenofovir/emtricitabine chemoprophylaxis
• Ensure drug treatment adherence to make sure that the prophylaxis is effective. This is done by checking blood levels of the antiretroviral drugs
• If the patient has symptoms that are consistent with an acute viral infection for less than four weeks, one should delay starting pre-exposure prophylaxis and reconfirm their HIV status
• Check the status of HIV if there is any doubt that the individual is missing the medications and yet engaging in high-risk sexual behavior
• Check for adverse effects of the antiretroviral medications
• Educate on adherence to medication use
• Monitor lifestyle and types of risky behaviors that increase the risk of acquiring HIV

Cost Benefit

Pre-exposure chemoprophylaxis is significantly less costly than the actual treatment of HIV infection, both in terms of duration of use and per dose. Pre-exposure chemoprophylaxis is prescribed to high-risk individuals and is supposed to be taken daily until the risk factors diminish; whereas, those who acquire HIV need lifelong HAART to prolong life. Further, HAART consists of multiple drug combinations which are prohibitively expensive; whereas pre-exposure chemoprophylaxis uses only one drug combination, which is relatively less costly. Unfortunately, surveys conducted by the CDC reported that in 21 out of the 31 countries, the cost of pre-exposure chemoprophylaxis was a major factor in the wider implementation of this treatment regimen (CDC, 2014). Infectious disease experts state that ultimately the cost-effectiveness of pre-exposure chemoprophylaxis will be determined by the final retail cost of the medication and how efficiently it can be delivered to the individuals who need it the most.

Demand for Pre-Exposure Chemoprophylaxis

While delivering pre-exposure chemoprophylaxis to prevent HIV is an admirable goal, what exactly is the demand? A recent multi-country survey of individuals at high-risk for HIV indicated that at least 70% of participants would most definitely use the treatment if it were available. In addition, another study from India revealed that close to 90% of men who have sex with men would use pre-exposure chemoprophylaxis if it were readily available.

Another study from the United Kingdom revealed that nearly 50% of men who have sex with men showed an interest in pre-exposure chemoprophylaxis, and it is believed that such an approach could prevent close to 7000 new HIV infections by the year 2020 (NHS, 2017).

Similar findings have been noted in Latin America among men who have sex with men, sex workers, and transgender women. Unfortunately in Latin America, despite the huge demand, only Brazil has a publicly available pre-exposure chemoprophylaxis program (WHO, 2017).

In England, the National Health Service has started to provide individual access to pre-exposure chemoprophylaxis in small clinical trials, which has led many other individuals to purchase generic versions of tenofovir and emtricitabine from online sources. Further, the British Council for Drug Safety has analyzed the online antiretroviral drugs and found them to be of similar quality and as effective as those sold in retail stores (NHS, 2017).

Adherence

For pre-exposure chemoprophylaxis to be successful, medication adherence is vital. While short-term clinical trials under controlled conditions have shown high adherence rates, data from outpatient clinics (outside of clinical trials) reveal that adherence can vary from 13% to 52%.

Factors that lead to low adherence include the following:

• Lack of availability of the drug regimen
• Individual’s lifestyle
• Exposure to abuse and violence within a relationship
• Stress
• Partner throwing away the pills
• Forgetfulness
• The stigma of being at risk for HIV
• Discrimination

Some clinics have started to use cognitive behavioral therapy for patients at risk for low adherence to improve adherence. So far there are no data to determine if this therapy can change the adherence rates. Two clinical trials are underway using a long-acting injectable antiretroviral formula to avoid the low adherence.[12]

• Burkitt lymphoma 

• Candidiasis

• Coccidioidomycosis and valley fever

• Cryptococcosis

• Cryptosporidiosis

• Cytomegalovirus

• Herpes simplex virus

• High grade malignant immunoblastic lymphoma

• MAC

• Toxoplasmosis

For individuals who have limited options for protecting themselves against HIV, pre-exposure chemoprophylaxis is both cost-effective and practical.

Several large trials have been conducted on pre-exposure chemoprophylaxis. In almost every study the risk of acquiring HIV was significantly lowered by 54% to 90%. In fact, if the data only included individuals who adhered to medication use, then the effectiveness of this drug combination is close to 100%. The most well-publicized PROUD trial conducted in the United Kingdom revealed that pre-exposure chemoprophylaxis decreased the risk of HIV transmission by 86% and there were no negative changes in the sexual behavior of the participants.

The first pre-exposure chemoprophylaxis studies were done in 2007, and since then many other studies have reported similar benefits. Data from France, Canada, Kenya, South Africa, and Uganda show that use of tenofovir/emtricitabine significantly decreases the risk of HIV in different scenarios. More importantly, these studies have not shown that use of pre-exposure chemoprophylaxis leads to reduced use of a condom or high-risk sexual behavior. The PROUD study conducted in the United Kingdom found no difference in the number of STDs or condom usage among individuals who were treated with pre-exposure chemoprophylaxis and those who were not treated. Fortunately, the few observational studies have not shown that high-risk sexual behavior occurs in the short term, but there are no data on long-term behavior.[13][14][15]

• Pre-exposure chemoprophylaxis involves the use of antiretroviral drugs taken daily by individuals who are HIV negative to protect themselves from the infection
• Current data indicates that when taken as prescribed, pre-exposure chemoprophylaxis profoundly reduces the risk of HIV infection
• Pre-exposure chemoprophylaxis has been shown to be cost-effective in individuals at high risk for HIV infection. Besides the United States, it is used in Europe, Brazil, Australia, Uganda, Kenya, and South Africa
• Pre-exposure chemoprophylaxis offers no protection against other sexually transmitted infections
• Pre-exposure chemoprophylaxis for prevention of HIV must be delivered as part of a comprehensive package that deals with STD prevention
• The effectiveness of pre-exposure chemoprophylaxis drops significantly if the individual has poor adherence with medication use

Despite awareness of the benefits of pre-exposure chemoprophylaxis, there remain many challenges ahead. Data suggest that less than 5% to 10% of high-risk individuals have access to this therapy in the United States and even fewer outside of North America. In the United States, despite the approval for pre-exposure chemoprophylaxis in 2012, universal adoption has been slow. Similarly, in Europe, the number of individuals at high-risk for HIV have not participated in the treatment by the thousands; they only number in the hundreds. Another US study showed that awareness of pre-exposure chemoprophylaxis in the United States is lowest among young black men who have sex with men.

Pre-exposure chemoprophylaxis has been fully approved in Australia, Brazil, Canada, and several African and European countries, but drug availability is a problem. In some countries, the drug regimen is too expensive, and in other countries, there are are no national guidelines established, which makes it difficult for healthcare workers to prescribe the treatment. Finally, in many countries, despite having a national healthcare system, the drug regimen often is not available for free. Even in Canada, with its well-established, free healthcare system, this drug regimen is not free, but there are plans to cover it under the universal healthcare system in the future.

The other limiting factor is lack of knowledge among healthcare workers about the availability of this treatment. While awareness has increased over the past five years among infectious disease experts, most other healthcare workers outside this specialty remain unaware.

To improve accessibility, in California, patients can get a prescription for pre-exposure chemoprophylaxis via a mobile app without even having to see a healthcare worker. The individual enters their data into an app, and the information is transmitted to a healthcare worker who then determines if the treatment is suitable. Of course, before a prescription is sent to the pharmacy, the individual must undergo blood testing to make sure that he or she is HIV negative.

In South Africa, two pilot programs called UChoose and PlusPills have been developed to reach out to young people who are at high risk for acquiring HIV.

The one other factor that has limited the use of pre-exposure chemoprophylaxis is that many people who could benefit from this treatment are not aware of it. Countless surveys done in Europe, Africa, and the United States indicated that only 30% of young men who have sex with men have heard about pre-exposure chemoprophylaxis. Individuals more likely to have heard about it usually are older, have some health insurance, are better educated, or reported as having acquired at least one STD in the past. [3][16][17](Level V)