Antiretroviral drugs are used to manage HIV and AIDS by attenuating the reproduction of the virus; they do not cure the virus, but rather limit its ability to duplicate itself. HIV is a RNA retrovirus, meaning it replicates itself by entering host cells, converting itself to DNA, then incorporating itself into that of the host cell. Antiretroviral drugs work by interrupting some part of this process, and drugs targeting different phases of the virus's life cycle are commonly taken together to most effectively debilitate it.
Currently, the most common regimen of antiretrovirals involves two nucleoside reverse transcriptase inhibitors (NRTIs) and one integrase nuclear strand transfer inhibitor (INSTI). Combination therapy is a relatively new innovation in the management of HIV and AIDS, beginning with Combivir (lamivudine and zidovudine) in 1997, developed by ViiV Healthcare, the same company responsible for Triumeq.
All three drugs in Triumeq are available separately, but combining multiple drugs into a single pill is appealing both because they are more effective in combination and because it improves patients' quality of life by reducing the burden of taking many pills throughout the day. The management of HIV with combined antiretroviral regimens is so effective that, despite the lack of a true cure, many patients live full, normal lives with few dangerous complications, in stark contrast to the 1980s when HIV was perceived as often imminently fatal. Today, at least in the developed world, HIV rarely progresses to AIDS, and most patients live to a normal life span so long as they are able to permanently suppress the virus with an antiretroviral regimen, though this necessitates a lifetime of medication and remains correlated with a higher incidence of renal, cardiovascular, and liver conditions.
NRTIs, including abacavir and lamivudine, inhibit reverse transcriptase, the enzyme that takes HIV's single-strand RNA and converts it to a double-strand DNA to be combined with the host's DNA. NRTIs accomplish this by binding with the RNA before it can be converted to DNA, but they also bind with the host's DNA and terminate the cell's reproduction altogether.
This complete halting of both the viral RNA and host DNA reproduction accounts for not only these drugs' antiviral properties, but also their unfortunately wide variety of side effects. Abacavir and lamivudine have similar mechanisms of action, but work by binding to different proteins of the RNA; abacavir is structurally similar to guanine, while lamivudine is similar to cytosine. By acting as analogues of two of the four proteins that build DNA and RNA, the two drugs working in tandem can more effectively paralyze the viral RNA's attempted reverse transcription.
INSTIs, such as dolutegravir, work by interrupting the integration of viral DNA into that of the host cell. After HIV's RNA creates a double-strand DNA molecule, it attempts to fully enter its host cell's genome by attaching itself to the DNA, thus reproducing whenever the host cell does. INSTIs halt the integration process by binding with integrase (the enzyme facilitating the attachment) before the viral DNA is able to.
The combination of abacavir, lamivudine, and dolutegravir was approved by the Food and Drug Administration in 2014. Of the three components, dolutegravir is the newest, approved for use in 2013; abacavir was developed in the late 1980s but approved in 1998, and lamivudine was first approved in 1995. The combination of the three drugs as Triumeq was developed by ViiV Healthcare, a collaboration between Pfizer and GlaxoSmithKline focused exclusively on drugs for treating HIV and AIDS. GSK owns 76.5% of ViiV Healthcare, while Pfizer owns just over 13%, and a Japanese company called Shionogi owns 10%. They have about 19% of the world's market share of drugs for HIV and AIDS, making them the second largest after Gilead Sciences, the developer of emtricitabine and tenofovir.
ViiV Healthcare is noteworthy for its commitment to not-for-profit distribution of its drugs in developing countries, and for licensing their drugs to companies manufacturing generics in order to reduce the cost. However, the drug remains very expensive for many patients, costing approximately $33,000 for a year's supply, and has earned the company millions. Triumeq is not among the drugs ViiV Healthcare has licensed as a generic, and this particular combination remains available only as a brand name product. ViiV Healthcare reported that in 2014, their group of twelve drugs for treating HIV and AIDS earned over $2 billion. GSK reported that, in 2014, following the FDA's approval of dolutegravir and the release of Triumeq and Tivicay (the brand name for pure dolutegravir), their profits rose by 15% after these two drugs brought in $512 million internationally.
Abacavir, lamivudine, and dolutegravir are each individually listed on the World Health Organization's Model List of Essential Medicines, a list of several hundred pharmaceutical drugs deemed critically important to public health and regarded as very safe if used as directed. The fixed-dose combination of the three is not on the World Health Organization's list, although a combination of abacavir and lamivudine is; this is likely because dolutegravir was discovered so recently.
The most common side effect of Triumeq is mild malaise, typically manifesting as headache, fatigue, nausea or lightheadedness. Sleep-related side effects, such as insomnia and nightmares, are also common. Moderate gastrointestinal distress, fever, rashes, or more significant lethargy are less common, and typically reported by patients with a heightened sensitivity to abacavir or dolutegravir, relatively rare complications discussed in more detail below.
While a very small percentage of patients taking Triumeq experience serious complications, it is for the most part very safe; only a small minority of patients require medical attention for side effects, and most side effects are only mild or moderate and subside as the patient's body adjusts to the drug.
Some patients exhibit hypersensitivity to abacavir; this is most common in patients with the HLA-B*5701 gene. In nine clinical trials where patients were not screened for this gene, 8% of patients exhibited sensitivity to abacavir, but in a trial where patients with this gene were excluded, only 1% of the respondents reported symptoms of hypersensitivity. Since this gene is so strongly predictive of hypersensitivity, the drug's manufacturer thus recommends screening all patients for it before beginning treatment, and advises those patients not to take it if alternatives are available.
Abacavir hypersensitivity can be serious and, in rare cases, fatal. The most dangerous reactions include anaphylaxis or the failure of one or more organs, but the most common symptoms are fever, rash, and nausea; most, though not all, hypersensitivity reactions involve fever or rash. Hypersensitivity symptoms most commonly occur within the first two to six weeks of treatment, but can potentially occur at any time while taking abacavir. In patients experiencing symptoms of hypersensitivity, they tend to grow more severe over time, but typically subside after stopping treatment. Resuming taking abacavir after stopping due to a hypersensitive reaction is particularly dangerous, and has been known to cause life-threatening drops in blood pressure. Patients who experience fever, rashes, or severe nausea after taking Triumeq or any drug containing abacavir should seek immediate medical attention.
Hypersensitivty to dolutegravir has also been reported. Its symptoms, as observed in clinical trials, seem to be similar to mild or moderate cases of abacavir hypersensitivity, but because dolutegravir is a much newer drug with a completely different mechanism of action, the frequency and potential severity of hypersensitivty to it is not entirely understood. It is currently not possible to determine whether a hypersensitive reaction to Triumeq is caused by abacavir or dolutegravir, and patients who experience a hypersensitive reaction with Triumeq are thus advised to avoid both drugs.
In very rare cases, Triumeq can cause damage to internal organs, typically in the aforementioned hypersensitive patients. Hepatitis, pancreatitis and kidney failure have been reported in less than 1% of patients. These are the drug's most severe side effects, and can be life-threatening if not immediately addressed. Drugs containing abacavir are not recommended for patients with preexisting liver dysfunction; patients coinfected with hepatitis B should be monitored particularly closely.
Another very rare but extremely serious side effect of Triumeq is lactic acidosis, an accumulation of lactic acid in the blood. Lactic acidosis can result in an extremely low blood pH level, and sometimes requires hemofiltration (filtration of the blood). Its symptoms include significant muscle pain or weakness, numbness or coldness in the arms or legs, shortness of breath and cardiac arrhythmia; patients experiencing these symptoms even mildly after taking Triumeq should be evaluated by a doctor and given a blood test immediately.
Many patients using antiretroviral drugs experience significant weight loss or gain. While relatively common, the mechanisms causing these changes and their long-term consequences are currently not thoroughly understood. Patients commonly lose weight in their face, or gain pockets of fat in unusual places, such as the upper back. Eating a healthy diet and exercising regularly should help mitigate these symptoms.
Some patients using Triumeq have reported experiencing psychological side effects, including depression, irritability and difficulty with concentration, though these symptoms could certainly be related to the stress of dealing with a serious chronic condition such as HIV, rather than being caused by the medication.
When used together as Triumeq, the drugs are taken as a single tablet containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine, taken orally once each day. It can be taken with or without food. Triumeq is distributed as a single light purple tablet with "572 Tri" printed on one side, coated in a thin film.
Patients also taking the antiretrovirals efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, the antiepileptic carbamazepine, or the antibiotic rifampin are recommended to take an additional 50 mg of dolutegravir 12 hours after taking Triumeq, since these drugs can reduce the body's concentration of dolutegravir.
Patients who miss a dose of Triumeq should take it as soon as they remember, unless their next dose is less than four hours away; patients should never take extra to make up for a missed dose.
Since it is distributed as a fixed dose taken once per day, the effects of an overdose with Triumeq have not been widely observed and are not thoroughly understood.
No interaction trials have been conducted with the combination of abacavir, dolutegravir, and lamivudine together as Triumeq, but many trials have examined the three components individually.
Several common minerals, including calcium, iron, aluminum, and magnesium, can interfere with the absorption of dolutegravir; Triumeq or dolutegravir should thus be taken at least two hours before or six hours after moderate amounts of any of these minerals are consumed. These minerals are found widely in vitamin supplements and common over the counter medicines, including antacids containing calcium carbonate and acetaminophen-based medicines with magnesium or aluminum hydroxide. Taking these in combination with Triumeq is not acutely dangerous, but it will reduce the drug's effectiveness.
Triumeq's manufacturer warns that it should never be taken alongside other drugs containing any of its three components, the similar HIV drug emtricitabine, or the arrhythmia drug dofetilide. The exception to this is for patients taking certain drugs that decrease the effectiveness of dolutegravir, who may need an additional dose of that drug; specific details on this case are listed above, in the Dosage section. Patients with a history of resistance to any of Triumeq's components may also need a supplemental dosage, and should discuss this with their doctor.
Triumeq should not be taken by patients who have moderate or severe liver disease, who have tested positive for the HLA-B*5701 allele, or who have ever had an allergic reaction to any of its three component drugs.
The most serious complications with Triumeq are usually associated with hypersensitivity to abacavir, described in detail in the Side Effects section. Patients must be screened for the HLA-B*5701 gene, since it is strongly predictive of hypersensitivity, and must tell their doctor about any history of allergic reaction to abacavir or similar antiretroviral drugs. Failing to disclose this information can, in rare cases, be extremely dangerous.
Patients should discuss liver and kidney problems with their doctors in detail before beginning Triumeq, particularly hepatitis B or C, because Triumeq can cause a dangerous exacerbation of viral hepatitis. The patients' alcohol use should also be discussed, since long-term alcohol abuse can predispose patients to undiagnosed liver problems, which may grow more severe after beginning Triumeq.
A small trial of methadone users suggested that Triumeq may decrease the effectiveness of methadone for a small minority of users, but the sample size of 11 was too small to be conclusive.
The effects of Triumeq on unborn babies are not known; pregnant women are recommended to take all of their HIV medications regardless to reduce the risk of transmitting the virus to their baby. Triumeq's effects on breast milk are not known, but women with HIV or AIDS are always advised not to breast feed their children, even if their baby was born without the virus, due to the risk of transmission. There is a registry for pregnant women taking antiretrovirals, hoping to collect data on these drugs' effect on pregnancies and prenatal development. Pregnant HIV patients taking Triumeq or similar drugs could make a significant contribution to pharmaceutical research by participating in this ongoing study.
While several other antiretroviral drugs are approved by the FDA for treating children and adolescents, including emtricitabine and efavirenz, Triumeq's manufacturers warn that is neither approved for nor intended for children. However, all three of its components are known to be safe for young patients - abacavir and lamivudine are used in children as young as three months old, and dolutegravir is FDA approved for patients over age 12.
Triumeq pills should be stored at room temperature, approximately 77 degrees Fahrenheit (25 Celsius), but can tolerate between 59 to 86 Fahrenheit (15 to 30 Celsius). While their manufacturer doesn't designate an acceptable humidity range, they do note that Triumeq must be protected from moisture, and thus must not be stored in bathrooms that become steamy during bathing. Triumeq must be kept out of the reach of children and pets.
Prescription to Triumeq is typically indefinite, but in the uncommon cases where a patient needs to stop taking it, it should be disposed of in dedicated medication return centers to prevent its entry into the water supply.
The combination of abacavir, lamivudine, and dolutegravir represents the newest generation of medication for HIV, and for most patients it is effective enough to turn the virus into a manageable chronic condition like diabetes that has no impact on life span. There is reason to be optimistic about the future of HIV treatment, and also to continue working to expand access to these drugs by reducing their cost and introducing them to the areas most in need.
While its manufacturer, ViiV Healthcare, has licensed many of their drugs as generics and committed to distributing them for no profit in the developing world, Triumeq remains available only as a brand name drug, making this highly effective treatment prohibitively expensive for many patients even in the United States and other highly developed countries. Abacavir and lamivudine are available as generic medications, but dolutegravir remains under patent and thus so do combination drugs containing it such as Triumeq. Debates about health insurers' coverage of patients with preexisting conditions are especially salient to those living with HIV and AIDS, because these conditions require a lifetime of medications which remain often unaffordable without insurance, and interrupting or changing therapies even briefly can be very dangerous.
Triumeq, like virtually all modern antiretrovirals, is thoroughly safe, so long as patients promptly report any side effects and are honest with their doctors about their medical history, particularly regarding liver issues, previous incidences of hypersensivity to antiretroviral drugs, and all other drugs and supplements they use. Its most serious side effects with hypersensitivty and organ damage are uncommon, but for a small percentage of patients can become very dangerous. Nonetheless, it is regarded as very safe for the vast majority of those who need it, sufficiently so that the World Health Organization has designated its components as essential to public health.