Which HIV Combination Therapy Should I Start With?

Genetic, Clinical and Even Personal Factors Play a Part in Choosing Wisely

Photo Credit: National Institute of Drug Abuse

With introducing newer generation drugs, choosing the right HIV combination therapy is often as simple as choosing one daily, all-in-one tablet versus another daily, all-in-one tablet. And in most newly treated patients, it is as simple as that—requiring little more than a couple of blood tests and a thorough review of medical history to ascertain which drug combo will work best for you as an individual.

However, making the right choice is not always about convenience. While having an all-in-one solution like Atripla, Complera or Genvoya might certainly make life easier from an adherence point of view, genetic, clinical or even personal factors often suggest alternate approaches to therapy.

Ultimately the aim of informed treatment is to individualize therapy so that your drugs work for as many years as possible with minimal side effects and maximal viral suppression (as measured by the HIV viral load). To do so requires evaluating the following treatment factors:

Types of Drugs Preferred in First-Line Therapy

Treatment guidelines have changed considerably in the course of the past decade, moving away from certain drugs (or classes of drugs) known to be more toxic or to be more prone to developing drug resistance.

In the current U.S. guidelines, greater emphasis has been placed on the use of integrase inhibitors (ISTIs) in first-line therapy, with four of the six preferred therapies incorporating the ISTI drugs darunavir (found in Triumeq and Tivicay), raltegravir (Isentress) or elvitegravir (found in Vitekta, Stribild, and Genvoya).

The rationale for the preferred status includes better tolerability, fewer treatment side effects, and far improved resistance profiles (meaning that they are better able to overcome any pre-existing drug resistance your virus may have). All preferred therapies are taken on a once-daily basis, an acknowledgment that ease of use is an important factor in maintaining optimal treatment adherence.

Genetic Makeup of Your Virus

There is no such thing as one type of HIV virus. In the course of HIV therapy, the virus will undergo continual mutations, some of which confer to drug resistance. As this mutated virus is passed from person to person, the resistance is also passed (a condition referred to as transmitted or acquired resistance).

As many as one in six newly infected persons in the U.S. will acquire resistance to at least one class of HIV drugs. Acquired multi-class drug resistance is also common.

In order to ensure your first-line therapy is able to overcome such barriers, genetic tests (commonly referred to as a genotyping) is performed to identify which mutations your virus has and whether those mutations confer resistance. Drug selection is based on a careful analysis of the genotypic results.

In resource-limited settings where genotyping is not routinely performed, drug choice is based on an educated assessment of (a) the known or presumed resistant variants within a particular geographic region and (b) the available drugs known to better overcome such resistance.

Physiological and Psychological Factors

Clearly, the overall health of the patient directs how treatment is commonly prescribed in persons with HIV. The immune status of the patient (as measured by the CD4 count) may motivate the use of one drug over the other. Some medical conditions can also exclude the use of certain antiretroviral agents, either because the drug can exacerbate a pre-existing condition or cause a flare-up of symptoms.

Among the examples:

  • The use of tenofovir is contraindicated in persons with severe kidney (renal) dysfunction as it can cause kidney failure in some patients. Such a condition might exclude the use of the tenofovir-containing drugs Viread, Truvada, Stribild, Complera, and Atripla.
  • Patients with clinical depression, anxiety, schizophrenia, bipolar disorder, or any other serious psychological/psychiatric condition might be warned of the use of efavirenz, a drug known to directly affect the central nervous system (causing vivid dreams, concentration problems and sleep disturbance). Any of these conditions could exclude the use of Sustiva and the efavirenz-containing drug Atripla.
  • Persons with known or diagnosed liver impairment (including those with hepatitis) should avoid any drugs which can exacerbate the condition. This is caused by the metabolism of these the drugs in the liver, which can lead to a build-up of toxic chemicals (a condition known as hepatotoxicity). The use of Aptivus (tipranavir) is contraindicated in such instances, as are a number of other antiretroviral agents in more serious manifestations of liver dysfunction.

Drug-Drug Interactions

Drug-drug interactions are common occurrences in a patient on HIV therapy, with some interactions requiring a change in dose and others require terminating either the HIV or associated drug.

One of the most common interactions involves drugs used to treat tuberculosis (TB), with no less than 13 antiretroviral drug molecules contraindicated for use with the TB drugs rifampin and rifapentine.

Similarly, a dozen HIV drugs are not be used along with some hepatitis C drugs, their combined use reducing the efficacy and outcomes of either one or both the drugs. The same applies to lipid-lowering drugs Mevacor (lovastatin) and Zocor (simvastatin), which should not be taken with many of the HIV protease inhibitor class drugs (PIs).

More surprisingly, perhaps, the over-the-counter herbal remedy St. John’s Wort is contraindicated for use with all HIV medications as it is known to significantly decrease the drug concentration in the bloodstream.

It’s important to always advise your doctor about any drugs, both prescribed and non-prescribed, that you are taking whether on a regular basis or not.

Lifestyle Factors and Other Considerations

Informed HIV treatment takes into account a person’s lifestyle and how treatment might negatively impact that lifestyle. And oftentimes it is not an easy call. Even in the most seemingly "simple" cases—where, for instance, irregular shift work might make the neurological effects of efavirenz intolerable—extra care should be taken to ensure that treatment is tailored as much to a patient’s sense of well-being as to the clinical outcomes.

Women of child-bearing age, for example, should be advised about the risk of efavirenz on fetal development and prescribed an alternate therapy should there be a possible pregnancy. 

In older patients, who as a population have a greater likelihood of kidney impairment, tenofovir may be replaced in order to avoid the potential for renal failure.

Patients on methadone therapy (used to treat opioid addiction) may be also advised to avoid efavirenz, as well as Viramune (nevirapine) and Kaletra (lopinavir/ritonavir), as they can diminish the effectiveness of both therapies. In the same breath, consideration needs to be made as to the use of simplified treatment options in a population where adherence consistency is often problematic.


Department of Health and Human Services (DHHS). "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents." Rockville, Maryland; accessed February 15, 2016.

Li, J.; Kim, D.; Linley, L.; et al. "Sensitive screening reveals widespread underestimation of transmitted HIV drug resistance." 2014 Conference on Retroviruses and Opportunistic Infections (CROI); Boston, Massachusetts. March 3-7, 2014; abstract 87.

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