Infectious Diseases

Initiating Antiretroviral Therapy

General (including evidence of efficacy)

When to start therapy

Overview

Over the past few years, there has been a dramatic shift towards treating all HIV-infected individuals, even those with relatively preserved CD4 T-cell counts. As a result, most people living with HIV should initiate antiretroviral therapy (ART). Strong endorsements for initiating ART regardless of CD4 count correlate with:

  1. Advancements in ART, such that treatments are now simpler and less toxic

  2. Accumulating evidence for long-term benefits of early ART initiation for seropositive individuals

  3. Pivotal data showing that treatment leads to a striking reduction in the likelihood of transmission to susceptible persons

The CD4 count should no longer be interpreted as an indicator of whether a person qualifies for ART; instead, it should be interpreted as a marker for the urgency of treatment. Patients with advanced HIV disease, especially with HIV-related complications, benefit tremendously from combination ART. However, even individuals with asymptomatic HIV and relatively robust CD4 counts experience long-term health benefits from earlier ART initiation as well as significantly reduced likelihood of HIV transmission to others. Per the Department of Health and Human Services (DHHS) Adult and Adolescent HIV Treatment Guidelines, all persons with HIV should be offered ART, regardless of CD4 count, to reduce morbidity and mortality associated with HIV (grade AI recommendation) and to reduce transmission to others (also grade AI).

On a case-by-case basis, ART may be deferred if a person is not yet able to adhere to daily medications; for these individuals, efforts should be made to overcome barriers to adherence and ART should be started once they are able to comply with daily ART. The most recent World Health Organization (WHO) HIV Treatment Guidelines similarly recommend ART for all HIV-infected persons, regardless of CD4 count, with priority given to those with low CD4 or stage III or IV clinical disease.

In recent years, new antiretroviral agents and single-tablet co-formulations have become available and there has been a reorganization of the list of recommended regimens for initial therapy. This review covers indications for initial ART, the baseline assessment, and selection of the optimal starting regimen.

When to start therapy: The patient with acute/recently acquired HIV infection

In patients with symptomatic acute HIV infection, there are no long-term clinical trials proving the benefit of initiating therapy versus observation. However, there are several lines of evidence supporting early initiation of ART for these individuals, including:

  1. Patients with symptomatic acute HIV appear to progress more rapidly as measured by CD4 decline and time to symptomatic HIV disease.

  2. In observational studies of patients with known dates of seroconversion, the time to reaching a predefined threshold for initiating ART (e.g., a CD4 cell count of 500 or 350) averages a few years. Such data indicates that treating acute HIV would add a relatively small incremental duration of ART onto a lifetime of treatment.

  3. A randomized prospective clinical trial comparing 48 weeks of treatment, 12 weeks of treatment, and observation found that the individuals who received 48 weeks of treatment had a more prolonged time to reaching a CD4 cell count of 350 than the other 2 treatment arms, as well as a lower post treatment interruption HIV RNA.

  4. A prospective observational cohort study found that patients treated within 4 months of HIV acquisition were more likely to achieve a CD4 cell count greater than 900 than those who deferred treatment until later.

  5. Patients with acute HIV generally have extremely elevated levels of HIV RNA in both plasma and genital secretions, and hence relatively high likelihood of transmitting HIV to others. Treatment rapidly lowers viral replication, reducing infectiousness.

  6. There is emerging evidence that patients treated during acute HIV infection may have a smaller viral reservoir compared to those treated with long established HIV. These individuals could conceivably be more conducive to HIV eradication.

  7. Symptoms during acute HIV infections may be severe (although transient); they disappear rapidly after starting ART.

In aggregate, these data support the use of ART in patients with acute HIV infection, especially if highly symptomatic. The International Antiviral Society USA (IAS - USA) and DHHS endorse such a recommendation in their most recent treatment guidelines. The DHHS guidelines also advocate the treatment of "recent" infection, defined as within 6 months of infection, and "early" infection, which encompasses acute and recent infection. The guidelines emphasize that an individual who initiates ART during early infection must be ready to take medications daily and, although several trials of treatment during acute infection have employed treatment interruptions, that strategy is not recommended in clinical practice given the risks of rebound viremia and other complications.

Initial regimens for patients with acute HIV are the same as those recommended for patients with established infection. If treatment is begun prior to receiving results of genotype resistance testing, regimens based on boosted protease inhibitors (PIs) are preferred over non-nucleoside reverse transcriptase inhibitors (NNRTIs) since resistance to the latter is more likely to be transmitted. If PIs cannot be used due to drug-drug interactions or other factors, integrase strand transfer inhibitor (INSTI) options are reasonable alternatives, given the low frequency of transmitted INSTI mutations, with a preference for dolutegravir given its relatively high barrier to resistance.

When to start therapy: The patient with established infection who is asymptomatic

As noted above, there has been a shift in recent years towards treating patients in the asymptomatic category.

In 2015, two momentous randomized clinical trials that examined the optimal timing of ART initiation were published; both found earlier ART initiation led to an approximate 50% reduction in morbidity and mortality as compared to delayed ART. First, the multinational START Study enrolled HIV-seropositive adults with CD4 count greater than 500 cells/ml and randomized participants to either immediate initiation of ART or delay of ART until the CD4 count dropped to below 350 cells/ml or an AIDS-associated clinical event occurred. The study was terminated early by the data safety monitoring board (DSMB) due to significantly better outcomes in those who started ART immediately. In particular, of the 4,685 study participants who were randomized, those who initiated ART with a CD4 greater than 500 cells/ml had lower risk of serious AIDS event, serious non-AIDS event, or death from any cause. This study is remarkable and decisive, especially because it enrolled participants from 35 countries, including both resource-limited and non-resource-limited settings.

Second, the TEMPRANO Study, conducted in the Ivory Coast, enrolled HIV-infected adults who had no indication to start ART (per guidelines at the time) and randomized participants to one of four arms: deferred ART, deferred ART plus isoniazid (INH) preventive therapy, early ART, or early ART plus INH preventive therapy. Over 2,000 HIV-infected adults were randomized and, like the START Study, results demonstrated significantly better outcomes in those who initiated ART immediately compared to those who deferred ART, with lower rates of serious HIV-related illness and lower mortality in those who initiated ART immediately. This trial also demonstrated benefit of INH preventive therapy, though that finding may not be applicable to all regions of the world.

The START and TEMPRANO results build on prior data suggesting a benefit to earlier initiation of ART. An observational cohort study conducted at multiple sites in North America found that patients initiating therapy with CD4 greater than 500 cells/ml experienced a nearly 2-fold reduction in risk of death. A randomized clinical trial done in Haiti demonstrated that among individuals with a CD4 cell count between 200-350 cells/ml, immediate start of ART led to improved survival compared with waiting until the CD4 cell count fell to 200 cells/ml or lower.

Furthermore, in a landmark study with the primary endpoint of HIV transmission to seronegative partners, asymptomatic individuals with a CD4 cell count between 350-550 cells/ml randomized to early therapy versus waiting until the CD4 fell to 250 cells/ml experienced:

  • Fewer clinical events (predominantly lower rates of tuberculosis [TB])

  • An astounding 93% reduction in the risk of HIV transmission to seronegative sexual partners

This finding that ART led to a substantial reduction in likelihood of transmission to HIV-uninfected individuals had significant impact on HIV treatment guidelines. One of the primary indications for early ART is to reduce the risk of transmission to others.

In addition to clinical benefits related to reduction in HIV complications and likelihood of transmission of the virus to others, several studies have also indicated a lower risk of non-AIDS complications (cardiovascular disease, liver disease in hepatitis C coinfected persons, malignancies, etc.) in patients whose CD4 cell count is relatively preserved. Possible explanations for these benefits include a reduction in inflammation and immune activation with earlier initiation of ART.

When to start therapy: The patient with an acute opportunistic infection

Although all patients with HIV-related opportunistic infections (OIs) clearly need ART, the optimal timing for ART initiation has been debated, and hence studied in several clinical trials. The dominant factor favoring earlier initiation of ART is the need to improve immune function rapidly; concerns about drug-drug interactions, pill burden, and the immune reconstitution inflammatory syndrome (IRIS) favor deferring therapy.

In a randomized clinical trial of patients with OIs other than TB, the strategy of starting ART within 2 weeks of OI diagnosis was compared with deferring therapy until 6-8 weeks later. The results of the study demonstrated a significant reduction in the risk of further AIDS complications or death for the early therapy arm. In addition, 3 studies of when to start treatment in patients with HIV and active TB found a clinical benefit to early ART initiation when the CD4 cell count is severely depleted (CD4 less than 50 cells/ml). While early treatment has been associated in some of the studies with an increased risk of IRIS, most (but not all) of these IRIS cases have been relatively mild and manageable with adjunctive therapy.

One exception to the above recommendation for earlier initiation of ART in the setting of an OI is cryptococcal meningitis; TB meningitis may also be an exception. Clinical trials focusing specifically on these two entities did not find benefit from earlier therapy; in the case of cryptococcal meningitis, earlier ART was associated with worse clinical outcomes in multiple studies. The largest trial to date of immediate (within 1-2 weeks) versus deferred ART initiation (at 5 weeks) in individuals with cryptococcal meningitis was stopped early due to increased mortality in the early ART group.

Based on the above clinical trials, it is recommended that ART in patients with an acute HIV-related OI typically start within 2 weeks of the OI diagnosis. For patients with cryptococcal meningitis, deferring ART initiation until 4-6 weeks of anti-infective therapy has been received is a reasonable option. For patients with TB, recommendations depend on level of CD4 count. Per the International AIDS Society (IAS-USA) guidelines, ART should be started by 2 weeks in those with CD4 count less than 50 cells/ml and within 2-8 weeks for those with higher CD4 counts. The optimal timing of ART for individuals with TB meningitis is unknown.

Summary recommendations: When to start antiretroviral therapy

Overall, the clinical benefits of ART in the vast majority of HIV-infected patients outweigh the risks. For those with severe immunodeficiency (CD4 count less than 350 cells/ml and especially less than 200 cells/ml or HIV-related complications) starting ART is a relatively urgent undertaking. Clinicians should plan to prescribe therapy sooner rather than later, with close follow-up, including clinical and laboratory monitoring. For persons with higher CD4 counts, ART is indicated to prevent progression of HIV disease and to avoid short and long-term complications, as well as to reduce the risk of transmission to others. The DHHS, IAS-USA, WHO, and other guidelines for treatment initiation agree that all HIV-infected individuals should be offered treatment and that the urgency of starting treatment increases as the CD4 count decreases.

Guidelines cite certain conditions which signify a greater urgency for starting ART; for example, the DHHS Guidelines state that the following indicate a more urgent need for ART: pregnancy, AIDS-defining condition, including HIV-associated dementia and AIDS-associated malignancies, most acute OI's, CD4 count below 200 cells/ml, HIV-associated nephropathy (HIVAN), acute/early HIV infection, or coinfection with hepatitis B or C. In select patients, treatment may be deferred if there are extenuating medical or psychosocial reasons that would make adherence to treatment difficult, especially if the CD4 count is relatively high; in that situation, barriers to adherence should be addressed first to optimize the individual's ability to adhere to daily medications.

Since the publication of the randomized clinical trial demonstrating that HIV treatment led to a 96% reduction in HIV transmission in serodiscordant couples, many patients with asymptomatic HIV and high CD4 cell counts should start treatment primarily to prevent transmission. This concept, referred to as "treatment as prevention," has become an essential component of patient counseling regarding benefits of ART initiation and adherence. According to DHHS guidelines, prevention of transmission is a strong indication for starting therapy (grade AI for preventing mother-to-child transmission and also grade AI for preventing transmission to sexual partners); IAS-USA guidelines also cite prevention of transmission as a strong indication for ART (grade AIa recommendation).

See Table I for Recommendations for initiating ART in treatment-naïve HIV-seropositive adults and adolescents.

Table I.

Recommendations for initiating ART in treatment-naïve HIV-seropositive adults and adolescents.

Baseline clinical and laboratory evaluation

At the time of HIV diagnosis, all HIV-infected patients entering care require a complete medical history, physical examination, and laboratory evaluation. Particular focus should be on concomitant conditions that might make HIV therapy more difficult for the patient to take successfully due to safety, tolerability, or other issues. A thorough list of concomitant medications is critical, as many drugs are metabolized through the cytochrome p450 system. Certain cytochrome enzymes are strongly influenced by PIs and cobicistat (generally inhibition more than induction) and, to a lesser extent, NNRTIs (generally induction).

Tests recommended at diagnosis are summarized below:

  • HIV antigen/antibody or antibody testing to confirm the diagnosis of HIV (if prior documentation is not available or if HIV RNA is below the assay’s limit of detection)

  • CD4 T-cell count

  • Plasma HIV RNA (viral load)

  • Complete blood count, chemistry profile, transaminase levels, blood urea nitrogen (BUN) and creatinine, urinalysis, and serologies for hepatitis A, B, and C viruses

  • Fasting blood glucose (or hemoglobin A1c) and serum lipids

  • Genotypic resistance testing

  • Testing for bacterial sexually transmitted infections (STI's), including gonorrhea, chlamydia, syphilis, and, in women, trichomonas

  • Toxoplasma IgG antibody (serology)

  • Screening for tuberculosis infection with tuberculin skin test (TST) or interferon-gamma release assay (IGRA)

  • HLA-B* 5701 test if considering use of abacavir in initial ART regimen

  • Glucose 6-phosphatase dehydrogenase (G6PD) enzyme level, to screen for deficiency, if dapsone is required for PCP prophylaxis

  • Cytomegalovirus (CMV) IgG antibody (serology) if low-risk for infection; individuals with high likelihood of prior infection (i.e., men-who-have-sex-with-men or injection drug users) are assumed to be CMV IgG positive

  • Varicella zoster virus (VZV) IgG (serology) if no history of chicken pox or vaccination

These tests should be obtained regardless of whether ART is started immediately.

As noted above, genotypic resistance testing is recommended for all patients to detect transmitted drug resistance. Rates of this baseline resistance among newly-diagnosed individuals vary according to region and risk factor for HIV acquisition. Across a variety of studies, the rate of resistance prior to starting therapy ranges from 5-15%. Resistance is usually single-class, though multiclass resistance is identified in rare instances. To date, guidelines do not recommend routine addition of baseline integrase resistance testing due to low documented rates of transmitted integrase resistance; however, if a patient is found to have extensive multiclass resistance on a baseline genotype resistance assay or if a patient has known exposure to an individual with integrase resistance or integrase inhibitor failure, many experts would add an integrase genotype to screen for concomitant transmitted integrase mutations.

In addition to the above recommended baseline tests, guidelines suggest several specific tests to screen for occult infection in asymptomatic individuals with low baseline CD4 counts. For example, OI guidelines in the United States state that some experts recommend a serum cryptococcal antigen assay (CrAg) for individuals with low CD4 count (less than 100 cells/ml or especially less than 50 cells/ml) given a chance of occult cryptococcal infection and risk of cryptococcal meningitis or IRIS after initiating ART. According to one study in the United States, the prevalence of cryptococcal antigenemia is 2.9% in individuals with CD4 less than 100 cells/ml and 4.3% with CD4 less than 50 cells/ml, and multiple studies have demonstrated that cryptococcal antigenemia portends a high likelihood of cryptococcal disease.

If the serum CrAg test is positive in an asymptomatic individual with low CD4 count, the next step in evaluation is a lumbar puncture with opening pressure to rule out occult cryptococcal meningitis. If the CSF analysis does not indicate cryptococcal meningitis, the patient should begin fluconazole for cryptococcal meningitis prophylaxis. Some experts also routinely obtain baseline ophthalmologic exam for individuals with CD4 count less than 50 cells/ml to screen for occult evidence of CMV retinal disease, and some also obtain routine mycobacterial blood cultures to screen for mycobacterium avium complex (MAC) infection in individuals with low CD4 counts, though there is no strong guidelines-based recommendation for this to date.

Medication adherence is strongly correlated with the likelihood of treatment success.

The most important factor to reduce the risk of HIV treatment failure and development of ART resistance is patient adherence. The use of once-daily regimens with lower daily pill burdens and generally fewer food/fluid requirements have made medication adherence easier for most patients.

Factors that correlate with reduced medication adherence are listed below:

  • Low levels of literacy

  • Certain age-related challenges (e.g., vision loss, cognitive impairment)

  • Psychosocial issues (e.g., depression, homelessness, inadequate social support, stressful life events, dementia, or psychosis)

  • Active (but not history of) substance abuse, particularly for patients who have experienced recent relapse

  • Stigma

  • Difficulty taking medication (e.g., trouble swallowing pills, daily schedule issues)

  • Complex regimens (e.g., pill burden, dosing frequency, food requirements)

  • Adverse drug effects

  • Treatment fatigue

In patients with asymptomatic HIV disease and higher CD4 cell counts, treatment may be deferred while efforts to reduce these impediments are undertaken, though ART should be initiated as soon the patient is ready to adhere to daily ART.

What to start

The recommendation to start ART in asymptomatic patients with relatively preserved CD4 cell counts would not be possible without the development of therapies that are safer, better tolerated, and less prone to option-limiting resistance. Importantly, the most toxic of the early ART agents, particularly stavudine (d4T), didanosine (DDI), zidovudine (AZT), indinavir, nelfinavir, and lopinavir are no longer widely used in developed countries; thus, complications such as lipoatrophy, lactic acidosis, peripheral neuropathy, pancreatitis, and severe diarrhea have decreased dramatically.

Several ART regimens that were used widely for many years have also fallen out of favor. For example, tenofovir disoproxil fumarate (TDF)-emtricitabine-efavirenz (Atripla) is no longer a recommended first-line agent in the United States and many other parts of the world and was demoted to the list of alternative regimens in the DHHS guidelines, primarily due to effects on mental health. A large study that compared this efavirenz-containing regimen to other first-line ART regimens found double the risk of suicidality or suicide attempt in those individuals who took the regimen containing efavirenz.

The PI atazanavir (Reyataz) has also fallen out of favor and off the list of first-line recommended regimens in developed countries due to tolerability issues. Side effects of atazanavir include indirect hyperbilirubinemia, which is not dangerous but can lead to jaundice, as well as nephrolithiasis and cholelithiasis; the medication also has more gastrointestinal side effects and drug-drug interactions than more modern agents. A recent clinical trial (ACTG 5257) compared ritonavir-boosted atazanavir to ritonavir-boosted darunavir and raltegravir, each with two NRTI's. In the trial, raltegravir performed better than the other agents in a combined endpoint of tolerability and virological efficacy; results were primarily driven by greater tolerability of raltegravir and more frequent treatment changes with atazanavir. The trial did not include dolutegravir, which has become a frequent choice for initial therapy, due to ease of dosing, relative scarcity of side effects or drug interactions, and relatively high barrier to resistance.

Moreover, newly developed "next generation" ARV agents induce lower rates of long-term side effects as compared to older agents. In particular, the novel NRTI tenofovir alafenamide (TAF), a tenofovir prodrug that leads to lower levels of tenofovir in plasma and higher levels in target cells as compared to TDF, leads to reduced risk of proximal tubulopathy and bone mineral density side effects and is now available in several co-formulated tablets.

In the DHHS Guidelines, recommended initial ART regimens have become consolidated into several categories:

  1. "Recommended Regimens," which the guidelines panel describes as regimens, "with durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use".

  2. "Alternative Regimens," which the panel describes as regimens that, "are effective and tolerable, but have potential disadvantages when compared with the recommended regimens, have limitations for use in certain populations, or have less supporting data from randomized clinical trials".

  3. "Other Regimens," which the panel describes as regimens that, "may have reduced virologic activity, limited supporting data from large comparative clinical trials, or other factors such as greater toxicities, higher pill burden, drug interaction potential, or limitations for use in certain populations".

Summaries of recommended and alternative initial antiretroviral regimen options as per the HHS and IAS-USA guidelines are in Table II and Table III respectively.

Table II.

HHS Recommended ART Regimens for Treatment-Naïve Adults and AdolescentsAdapted from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf

Table III.

IAS-USA: Recommended Agents for Initial Antiretroviral Therapy Adapted from: http://jama.jamanetwork.com/article.aspx?articleid=1221704

Regimen selection: General considerations

The DHHS Adult and Adolescent Treatment Guidelines list several options as recommended initial ART regimens for treatment-naïve (never before treated) adults (separate guidelines outline the recommended options for pediatric patients and pregnant women, which will not be reviewed in detail here). All of the recommended first-line ART options are composed of three antiretroviral agents, including two NRTI's (the "backbone") plus a third drug "anchor." The DHHS guidelines cite five different options for the third drug anchor, the majority of which are from the integrase strand transfer inhibitor (INSTI) class of ARV's (dolutegravir, raltegravir, and elvitegravir) and one of which is from the PI class (darunavir). Some of these third drug anchor options also require a pharmacokinetic "booster" in order to increase drug levels and allow co-formulation (the "booster" may either be ritonavir or cobicistat). The NRTI's that are included in the list of recommended options are TDF, TAF, abacavir, emtricitabine, and lamivudine. The list of recommended regimens includes:

  • Dolutegravir plus either TDF/emtricitabine or TAF/emtricitabine, or combined with abacavir/lamivudine (use of abacavir assumes documented negative HLA-B*5701 status)

  • Raltegravir plus either TDF/emtricitabine or TAF/emtricitabine

  • Elvitegravir boosted by cobicistat and combined with TDF/emtricitabine or TAF/emtricitabine

  • Darunavir boosted by ritonavir plus either TDF/emtricitabine or TAF/emtricitabine

Of these recommended regimen options, there are three single-tablet regimens (STRs). These single-tablet co-formulations, which provide a complete regimen in one tablet per day, include: abacavir/lamivudine/dolutegravir (Triumeq), elvitegravir/cobicistat/TDF/emtricitabine (Stribild), and elvitegravir/cobicistat/TAF/emtricitabine (Genvoya). An advantage of the STR abacavir/lamivudine/dolutegravir is the high barrier to resistance of dolutegravir, though prior to initiating any regimen with abacavir it is necessary to check an HLA-B*5701 test; abacavir should only be prescribed if the result is negative because positivity indicates risk of a hypersensitivity reaction that can be life-threatening.

The IAS-USA guidelines emphasize that the optimal initial ART regimen includes an INSTI (dolutegravir, raltegravir, or elvitegravir) due to enhanced tolerability as compared to a boosted PI or NNRTI, and includes TAF instead of TDF to reduce the risk of long-term renal and bone toxicity. Therefore, if insurance coverage and access are not barriers, the optimal initial ART regimen likely includes an INSTI plus an NRTI combination that includes TAF. In patients with renal insufficiency, TAF may be used as long as the creatinine clearance is above 30 ml/min.

It is important to remember that several ART agents (dolutegravir, cobicistat, and the NNRTI rilpivirine, which is a part of multiple DHHS alternative regimens) block tubular secretion of creatinine and thereby are expected to cause a small rise in serum creatinine over the first 4-8 weeks of ART, which does not represent a decrease in actual glomerular filtration rate (GFR), even though estimated GFR will decrease. If the serum creatinine rises significantly (more than approximately 0.4) or continues to rise after 4-8 weeks, an evaluation for other causes of renal function decline should be considered.

These first-line recommended regimens all have documented efficacy in numerous clinical trials, and thus the choice of regimen is largely individualized to each patient, based on factors such as pill burden, potential side effects, medical comorbidities, barrier to resistance of the medications and likelihood of ART adherence, food requirements, cost or insurance access, patient preference, and other factors.

Examples of some of the pros and cons of these first-line recommended agents include:

- Dolutegravir: small once-daily pill that has a high barrier to resistance and relatively few side effects and drug-drug interactions (though can cause headache and insomnia, blocks tubular secretion of creatinine, and has some drug-drug interactions including cation-containing vitamins and antacids as well as metformin).

- Raltegravir: relatively well-tolerated with few drug-drug interactions, though at this time is only available as a twice-daily formulation and has a relatively low barrier to resistance as compared to an agent such as dolutegravir.

- Elvitegravir: well-tolerated with few drug-drug interactions, though generally administered as a co-formulation with cobicistat, which can induce gastrointestinal side effects and does carry risk of numerous drug-drug interactions.

- Darunavir: once-daily for treatment-naïve individuals with high barrier to resistance, though must be given with a booster, such as ritonavir, which causes more gastrointestinal side effects and drug-drug interactions than other options.

- TDF: long history of clinical experience and clinical trial data confirming virologic efficacy and available as part of a number of co-formulations, plus has some lipid-lowering characteristics, but carries higher risk of renal side effects (most commonly a proximal tubule wasting syndrome which generally manifests as proteinuria and phosphate wasting) and bone toxicity (bone mineral density loss) as compared to other ART agents, plus dose must be reduced in the setting of renal insufficiency.

- TAF: as compared to TDF, induces less renal proximal tubule wasting effects and bone mineral density loss and has been shown to be effective in multiple clinical trials, but has less favorable lipid effects as compared to TDF (likely due to lower circulating plasma levels of the active metabolite) and less clinical experience to date.

- Abacavir: requires HLA-B*5701 testing prior to use and data suggest that it may increase risk of ischemic cardiovascular events (though data are conflicting and controversial); also does not treat hepatitis B (whereas TDF and TAF are effective anti-hepatitis B agents) and may be less efficacious in individuals with high viral loads when combined with certain other ARV agents (though this does not seem to be the case with currently recommended first-line ART combinations).

The DHHS Adult and Adolescent Treatment Guidelines also list several ART combinations as alternative regimens for treatment-naïve individuals. These regimens include several additional co-formulated single-tablet regimens and other co-formulated options. Notably, the NNRTI options efavirenz and rilpivirine are included in this list of alternative options:

  • Efavirenz co-formulated with TDF/emtricitabine

  • Rilpivirine co-formulated with TDF/emtricitabine or TAF/emtricitabine

  • Darunavir co-formulated with the booster cobicistat plus either TDF/emtricitabine or TAF/emtricitabine

  • Darunavir co-formulated with the booster cobicistat or given with the booster ritonavir, plus the co-formulated abacavir/lamivudine

  • Atazanavir co-formulated with the booster cobicistat or given with the booster ritonavir, plus TDF/emtricitabine or TAF/emtricitabine

Of these alternative regimen options, there are three STR options: efavirenz/TDF/emtricitabine (Atripla), rilpivirine/TDF/emtricitabine (Complera), or rilpivirine/TAF/emtricitabine (Odefsey). The efavirenz-containing combination is listed as an alternative and not recommended option primarily because the medication can cause or worsen mental health issues; a trial that compared efavirenz-based therapy to other regimens for treatment-naïve individuals found that those who took efavirenz had twice the rate of suicidality (including suicidal ideation or attempt). Additionally, the efavirenz-based regimen may be more difficult for individuals to adhere to as compared to other options (efavirenz should be taken on a relatively empty stomach at night and can cause central nervous system side effects like insomnia, vivid dreams, and morning grogginess) and it also has a low barrier to resistance. The rilpivirine-containing co-formulations are listed as alternative as opposed to recommended options because of data demonstrating that they are less likely to be effective for individuals with advanced HIV disease (defined as CD4 count below 200 cells/ml or HIV RNA level above 100,000 copies/ml); additionally, rilpivirine must be taken with a meal and cannot be taken with a proton pump inhibitor (PPI).

Regimen selection: Specific patient scenarios

Examples of individual patient scenarios, with accompanying considerations for optimal initial regimen options, are listed below. Prior to starting any regimen, it is important to review a patient's medication list for potential drug-drug interactions; significant interactions are listed in each ARV's prescribing information or in the DHHS treatment guidelines. The DHHS guidelines also provide greater detail as to the pros/cons of each regimen with each of these specific patient scenarios:

  1. Suboptimal adherence likely or possible. Multiple prospective studies have demonstrated that virologic failure on regimens containing a ritonavir-boosted PI is less likely to be accompanied by resistance than when the initial treatment contains an alternate agent. Regimens containing dolutegravir also seem to have a relatively high barrier to resistance; to date, development of dolutegravir resistance in individuals starting initial therapy with two NRTI's plus dolutegravir has not been reported, even in the setting of virological failure. Regimens with the other INSTIs, elvitegravir or raltegravir, do not share this quality, and develop resistance more readily. Therefore, for an individual who may have issues with adherence but needs ART, a combination that includes dolutegravir or boosted darunavir would be preferred.

  2. Advanced HIV disease, specifically HIV RNA greater than 100,000 cop/mL and/or a low CD4 count. Certain regimens have demonstrated a higher rate of virologic failure in this subset of patients. For example, when abacavir/lamivudine was compared with TDF/emtricitabine (with either boosted atazanavir or efavirenz), a pre-treatment HIV RNA greater than 100,000 copies/mL or a CD4 less than 50 cells/ml significantly increased the risk for virologic failure for the abacavir/lamivudine arms. There seem to be exceptions to this rule, such as abacavir/lamivudine with dolutegravir or abacavir/lamivudine plus boosted darunavir, which perform well even in individuals with advanced HIV. It is especially important to avoid rilpivirine if the current HIV RNA is greater than 100,000 copies/mL or CD4 count less than 200 cells/mL. Any of the recommended regimen options would be reasonable to choose in this scenario.

  3. Sexually-active women of childbearing potential either desiring pregnancy or not using reliable contraception. The teratogenicity potential of efavirenz is controversial, with early non-human primate studies suggesting the drug caused neural tube defects, although later large database studies did not confirm this finding. Current recommendations in developed countries are to avoid efavirenz in women of child-bearing potential, given the possibility of teraogenicity. If a woman of child-bearing potential desires pregnancy or is not using reliable contraception, efavirenz should definitely be avoided. Recommended regimens: consider initiating therapy with a regimen that is recommended for pregnant women (see below).

  4. Pregnant women. All pregnant women should receive ART to prevent transmission of HIV to the fetus. Recommended regimens include: TDF/emtricitabine (or zidovudine/lamivudine or abacavir/lamivudine, if patient is HLA-B* 5701 negative) plus raltegravir or ritonavir-boosted atazanavir (ritonavir-boosted darunavir is also a reasonable option, but per current guidelines should be dosed twice daily during pregnancy). Efavirenz can be used after the first 8 weeks of pregnancy because by that time the neural tube has already formed. Similarly, if a woman happens to become pregnant while taking efavirenz and is doing well on the medication with a suppressed viral load, it is generally not necessary to change the efavirenz, because by the time the pregnancy has been detected, 8 weeks or more has likely passed and the neural tube has likely already formed. However, there may be other reasons to consider a change of efavirenz to other options, such as neuropsychiatric side effects. The DHHS offers full guidelines for treatment of HIV-infected pregnant women, which provides more detail as to the pros/cons of various ART regimens during pregnancy.

  5. Preexisting renal disease. Patients with renal disease appear to be at greater risk of developing TDF-related renal dysfunction, so in general TDF should be avoided. If TDF is required, dose reduction is advised if calculated GFR is less than 50 ml/min/1.73 m2. Recommended alternatives include TAF (as long as the GFR is above 30 ml/min/1.73 m2) or abacavir (as long as the HLA-B*5701 assay result is negative).

  6. Preexisting cardiovascular disease (CVD) or multiple cardiovascular disease risk factors. Some studies have shown an association between abacavir use and an increased risk of ischemic cardiovascular events. As such, abacavir should be used with caution in those patients with known CVD, or at high risk for CVD, and some experts would avoid abacavir in this setting assuming there are reasonable alternatives. If a patient has hyperlipidemia, certain ARV agents may be more favourable than others (e.g., raltegravir, dolutegravir, or rilpivirine are more lipid-friendly anchor drugs than boosted PI's or boosted elvitegravir).

  7. Preexisting psychiatric disease. The most important factor is to avoid efavirenz, which can exacerbate underlying mental health issues and for this reason is no longer on the list of recommended regimens. Furthermore, some psychiatric medications interact with ritonavir-boosted PIs or cobicistat, so a thorough review of potential drug-drug interactions is important and it may be optimal to avoid regimens that include cobicistat or PIs. The DHHS guidelines also recommend avoiding efavirenz in the setting of HIV-associated dementia, as the neuropsychiatric side effects may complicate assessment and monitoring of the dementia symptoms.

  8. Hepatitis B coinfection. The combination tablets TDF/emtricitabine and TAF/emtricitabine both provide two drugs active against hepatitis B, whereas other NRTI options (such as abacavir/lamivudine) have only one, risking hepatitis B resistance to lamivudine or emtricitabine. Therefore, the recommended NRTI combination in this scenario is TDF/emtricitabine or TAF/emtricitabine; if TDF or TAF are not available or contraindicated due to renal function, the alternative option is to give abacavir/lamivudine and add the anti-hepatitis B agent entecavir.

  9. Hepatitis C coinfection. In the era of directly acting antivirals (DAA's) for hepatitis C, toxicity of hepatitis C therapy has markedly decreased; however, drug-drug interactions with antiretrovirals exist, and a careful review of potential interactions is important before initiating hepatitis C therapy. A summary of key interactions is available in the DHHS guidelines or in the prescribing information for each DAA. In general, two NRTI's plus raltegravir or dolutegravir tend to be the regimens with the fewest interactions, though this is an evolving field.

  10. Tuberculosis (TB) co-infection. Significant drug-drug interactions between antimycobacterial drugs and ARV agents exist, so a thorough review of these interactions is necessary for any patient with HIV-TB coinfection. The most significant interactions are generally with the rifamycins; rifampin can be safely combined with standard-dose efavirenz, but that ARV is no longer a recommended option for HIV treatment. Other options include rifampin combined with raltegravir or dolutegravir, but rifampin lowers levels of these drugs so the doses must be increased (the dose of raltegravir can be increased to 800 mg twice-daily or the frequency of dolutegravir dosing can be increased to 50 mg twice-daily, though this is not recommended if any INSTI resistance-associated mutations are present).

  11. Treatment initiation prior to genotype resistance results. In some situations, there may be benefit to starting ART without waiting for the baseline genotype resistance assay results (such as with certain OI's or in late pregnancy). In this scenario, initiation of a boosted PI (such as ritonavir or cobicistat-boosted darunavir) or dolutegravir would be reasonable, as transmitted PI or INSTI resistance is rare and both of these agents have a high barrier to resistance and high likelihood of efficacy.

  12. Difficulty with food intake. Certain ART regimens must be taken with food, so if a patient has difficulty swallowing food or irregular intake due to food insecurity or other issues, certain regimens may be easier to adhere to than others. For example, raltegravir and dolutegravir-based therapy can be taken with or without food, whereas the elvitegravir-based options and boosted PI-based options should be taken with some food to enhance absorption and rilpivirine should be taken with a full meal. Therefore, raltegrafvir or dolutegravir would be preferred in this setting.

Newer treatment options

The newest INSTI, dolutegavir, has many ideal characteristics as an ARV agent; it is highly potent with a high barrier to resistance, generally well tolerated, and requires a small daily dose (and hence comes in a small once-daily tablet). In addition, it retains activity in the setting of some integrase resistance mutations selected by raltegravir and elvitegravir.

When compared to treatment with two NRTI's plus efavirenz or boosted darunavir for initial therapy, virologic efficacy rates were superior with dolutegravir, though superiority was largely driven by tolerability. When compared to initial treatment with two NRTI's plus raltegravir, virologic efficacy rates with dolutegavir were non-inferior. Dolutegravir, like rilpivirine, cobicistat and trimethoprim, blocks tubular secretion of creatinine and thereby causes benign minor serum creatinine elevations in the first 1-2 months of treatment; serum creatinine then stabilizes and this change to estimated GFR does not reflect a change in actual GFR and does not mandate a change to therapy. This expected effect on serum creatinine must be differentiated from TDF renal toxicity if a patient is also taking TDF; signs of TDF toxicity include an increase in serum creatinine of 0.4 or more, a rise in serum creatinine that worsens beyond the first 1-2 months of taking the medications, or a rise in serum creatinine that is accompanied by non-gap acidosis, proteinuria, glycosuria, low serum phosphate, elevated fractional excretion of phosphate, or other markers of a proximal tubule wasting syndrome.

Certain drug-drug interactions or a history of INSTI resistance mandate that dolutegravir be dosed twice-daily, instead of once-daily. Dolutegravir is available as a co-formulated, single-tablet regimen of abacavir/lamivudine/dolutegravir (Triumeq), which is an option if a patient has documented HLA-B*5701 negativity (due to the abacavir component).

The most recent ARV approvals involve the novel NRTI agent tenofovir alafenamide (TAF), which is a tenofovir prodrug that achieves higher levels in target cells and lower circulating plasma levels (and thus lower levels in the kidneys and bones). This new NRTI has been studied as part of initial HIV therapy, simplifications of ART, switches of ART in the setting of mild to moderate renal insufficiency, and for HIV-hepatitis B coinfection treatment. It is now approved and available in the United States and some other parts of the world as a component of the co-formulated tablets TAF/emtricitabine (Descovy), TAF/emtricitabine/elvitegravir/cobicistat (Genvoya), and TAF/emtricitabine/rilpivirine (Odefsey).

The first two (TAF/emtricitabine and TAF/emtricitabine/elvitegravir/cobicistat) are part of several first-line recommended options for treatment-naïve individuals and are also recommended as part of a simplification strategy for individuals with suppressed viral load for at least 6 months on other recommended regimens (assuming there is no history of treatment failure or resistance to any of the components of the single-tablet regimen).

TAF/emtricitabine/rilpivirine is listed as an alternative regimen option for treatment-naïve individuals because, as with other rilpivirine-containing regimens, it is less likely to be efficacious in the setting of a high viral load (above 100,000 copies/ml) or low CD4 count (below 200 cells/ml). TAF/emtricitabine/elvitegravir/cobicistat has also been studied as part of a simplification strategy for individuals with heavy ARV treatment experience and multiclass ARV resistance (in this study, the co-formulated tablet was combined with once-daily darunavir, though this study is yet to be published). When compared to regimens that contain TDF, the TAF co-formulations seem to lead to lower rates of renal proximal tubule wasting and bone mineral density loss though are less favourable in terms of serum lipid effects.

Additional co-formulations and novel ARV's are being studied and may attain approval in the near future. For example, a co-formulation of TAF/emtricitabine/darunavir/cobicistat is in development. Agents in new classes of ARV are being developed, such as an attachment inhibitor and a maturation inhibitor. Finally, several novel, long-acting, injectable antiretroviral drugs are being studied for both HIV treatment and prevention, including long-acting rilpivirine and a long-acting dolutegravir analog called cabotegravir.

Recommended follow-up and monitoring

Clinical and laboratory monitoring are both important after starting antiretroviral therapy. Since many subjective and laboratory adverse effects occur within the first several weeks of treatment, we typically schedule a follow-up clinical visit within 2-4 weeks of treatment initiation. Such visits can be used to query about side effects, review medication adherence, and obtain blood tests to assess both treatment response and medication toxicity such as elevated liver enzymes.

Treatment rapidly reduces the HIV RNA (viral load), and hence values will generally be at least 2 log (100-fold) less than baseline when measured after 2-4 weeks of treatment. Failure to detect a decline of at least 0.5 log (three-fold) from baseline strongly suggests medication non-adherence.

Laboratory testing for HIV RNA should be done at 2-8 weeks (4 weeks in typically chosen), then every 4-8 weeks until the level is less than the limit of detection of the assay (generally less then 40-50 copies/mL), at which point monitoring can be changed to every 3-6 months. By week 24 of therapy, the HIV RNA should be below the limits of detection of the assay in most patients; those who initiated therapy with a higher baseline HIV RNA level may take longer. Newer HIV RNA assays measure as low as 20-40 copies/mL, and hence are more sensitive than prior tests. As a result, patients who are on successful therapy may periodically have results in the detectable range. However, in these patients who have transient elevations of viral load – sometimes referred to as “blips” – the occurrence of resistance and treatment failure is unusual. One set of treatment guidelines suggests using a confirmed HIV RNA greater than 200 copies/mL as the criterion for virologic failure.

The CD4 count, while a marker for risk of OIs and urgency of ART initiation, is not as accurate a marker for ART response or adherence as viral load. The CD4 T-cell level is typically monitored after initiation of ART to assess immune rebound and, for individuals requiring OI prophylaxis, to determine when it becomes safe to discontinue prophylaxis. Current guidelines recommend rechecking the CD4 count every 3-6 months after ART initiation during the first two years, or until the CD4 reaches 300 cells/mL; at that point, frequency of checks can be reduced to annual. Once the CD4 is greater than 500 cells/mL with a routinely suppressed HIV RNA, checks of the CD4 count become optional, assuming the patient remains adherent to ART and clinically stable with a suppressed viral load. Several analyses have shown that more frequent monitoring of the CD4 count than this does not change clinical outcomes; in addition, decreasing the frequency of CD4 testing can decrease costs of care, as well as patient anxiety, which frequently reflects minor fluctuations in the CD4 level.

A typical CD4 improvement is 50–150 cells/mm3 per year, with increases on the higher end of this range (or even greater) in the first year of treatment. After many years of virologically suppressive treatment, a CD4 plateau usually is reached. Some patients – in particular those with very low baseline CD4 cell counts, slower CD4 slope, cirrhosis, and older age – have a blunted increase in their count despite virologic suppression. While some regimens induce a more favorable immunologic response to treatment than others, there is no evidence that changing a successful ARV regimen will improve the CD4 response in a clinically meaningful way, and such switches are not recommended.

Categories of Recommendation

Level A: Good scientific evidence suggests that the benefits of the clinical service substantially outweigh the potential risks. Clinicians should discuss the service with eligible patients.

Level B: At least fair scientific evidence suggests that the benefits of the clinical service outweighs the potential risks. Clinicians should discuss the service with eligible patients.

Level C: At least fair scientific evidence suggests that there are benefits provided by the clinical service, but the balance between benefits and risks are too close for making general recommendations. Clinicians need not offer it unless there are individual considerations.

Level D: At least fair scientific evidence suggests that the risks of the clinical service outweighs potential benefits. Clinicians should not routinely offer the service to asymptomatic patients.

Level I: Scientific evidence is lacking, of poor quality, or conflicting, such that the risk versus benefit balance cannot be assessed. Clinicians should help patients understand the uncertainty surrounding the clinical service.

Quality of Evidence

Level I: Evidence obtained from at least one properly designed randomized controlled trial.

Level II-1: Evidence obtained from well-designed controlled trials without randomization.

Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.

Level II-3: Evidence obtained from multiple time series designs with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.

Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

What's the evidence for specific management and treatment recommendations?

"Department of Health and Human Services, Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents". http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

Gunthard, HF, Saag, MS, Benson, CA. "Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society–USA Panel". JAMA. vol. 316. 2016. pp. 191-210.

"European AIDS Clinical Society: Clinical management and treatment of HIV-infected patients in Europe". http://www.europeanaidsclinicalsociety.org/guidelines.asp.

"Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents: Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America". http://aidsinfo.nih.gov.

(The above four sources, which provide guidelines for treatment and prevention of HIV infection and opportunistic infections, are updated frequently, extensively referenced, and available free of charge online.)

Lundgren, JD, Babiker, AG, Gordin, F. "Initiation of antiretroviral therapy in early asymptomatic HIV infection". N Engl J Med. vol. 373. 2015. pp. 795-807.

(Treatment-naïve individuals with CD4 count above 500 cells/ml were randomized to start ART immediately or wait until the CD4 count declined to below 350 cells/ml or an AIDS-related illness occurred; early ART led to reduced rates of serious AIDS-related or non-AIDS-related illness.)

Danel, C, Moh, R, Gabillard, D. "A trial of early antiretrovirals and isoniazid preventive therapy in Africa". N Engl J Med. vol. 373. 2015. pp. 808-22.

(Treatment-naïve individuals who did not meet guidelines for initiating ART at the time were randomized to deferred ART deferred ART plus isoniazid preventive therapy [IPT], immediate ART or immediate ART plus IPT; early ART led to lower rates of severe illness or infection and death as compared to deferred ART even in those with CD4 count above 500 cells/ml.)

Severe, P, Juste, MA, Ambroise, A. "Early versus standard antiretroviral therapy for HIV-infected adults in Haiti". N Engl J Med. vol. 363. 2010. pp. 257-265.

(Asymptomatic patients with CD4 cell counts between 200-350 were randomized to treatment versus observation; the treatment arm experiences significantly greater survival and fewer infectious complications than the observation group.)

Kitahata, MM, Gange, SJ, Abraham, AG. "Effect of early versus deferred antiretroviral therapy for HIV on survival". N Engl J Med. vol. 360. 2009. pp. 1815-1826.

(In this observational cohort study from multiple sites across North America, starting treatment before the CD4 fell to less than 500, was associated with significantly improved survival.)

Le, T. "Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy". N Engl J Med. vol. 368. 2013. pp. 218.

(In a prospective cohort study of acute or recently acquired HIV infection, those who started treatment within 4 months of HIV acquisition, were more likely to achieve a CD4 cell count greater than 900.)

Riddler, SA, Haubrich, R, DiRienzo, AG. "Class-sparing regimens for initial treatment of HIV-1 infection". N Engl J Med. vol. 358. 2008. pp. 2095-2106.

(Efavirenz-based treatment was more effective than Lopinavir/r-based regimens; virologic failure on the latter, however, was less likely to lead to resistance.)

Ortiz, R, Dejesus, E, Khanlou, H. "Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48". AIDS. vol. 22. 2008. pp. 1389-1397.

(Once-daily darunavir/r was non-inferior to lopinavir/r when given with TDF/FTC; darunavir/r treated patients also had a lower rate of diarrhea.)

Lennox, J, DeJesus, E, Lazzarin, A. "Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomized controlled trial". Lancet. vol. 374. 2009. pp. 796-806.

(Treatment with raltegravir was non-inferior to efavirenz when combined with TDF/FTC; raltegravir incurred fewer side effects.)

Zolopa, A, Andersen, J, Powderly, W. "Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial". PLoS One. vol. 4. 2009. pp. e5575.

(In patients with acute HIV-related opportunistic infections, early ART led to reduced progression to other AIDS events or death compared with starting treatment 4-6 weeks later. Tuberculosis was excluded from qualifying OIs.)

Sax, P, Tierney, C, Collier, A. "Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy". N Engl J Med. vol. 361. 2009. pp. 2230-2240.

(In patients with pre-treatment HIV RNA greater than 100,000, treatment with abacavir/lamivudine led to a nearly two-fold increased risk of virologic failure compared to tenofovir/emtricitabine whether given with efavirenz or atazanavir/r.)

Daar, ES, Tierney, C, Fischl, MA. "Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1: a randomized trial". Ann Intern Med. vol. 154. 2011. pp. 445-456.

(Initial therapy with atazanavir/r was not demonstrably different from efavirenz when combined with either TDF/FTC or ABC/3TC.)

Cohen, CJ, Andrade-Villanueva, J, Clotet, B. "Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomized, non-inferiority trial". Lancet. vol. 378. 2011. pp. 229-237.

(In treatment naïve patients, a rilpivirine-based regimen was noninferior to one with efavirenz. Rilpivirine was better tolerated, but associated with a higher rate of virologic failure in patients with HIV RNA greater than 100,000 copies per mL.)

Sax, PE, DeJesus, E, Mills, A. "Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomized, double-blind, phase 3 trial, analysis of results after 48 weeks". Lancet. vol. 379. 2012. pp. 2439-2448.

DeJesus, E, Rockstroh, J, Henry, K. "Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomized, double-blind, phase 3, non-inferiority trial". Lancet. vol. 379. 2012. pp. 2429-2438.

(In these two clinical trials, co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir was noninferior to two different widely used first-line regimens: TDF/FTC/EFV and TDF/FTC + atazanavir/ritonavir.)

Boulware, DR, Meya, DB, Muzoora, C. "Timing of antiretroviral therapy after diagnosis of crytptococcal meningitis". NEJM. vol. 370. 2014. pp. 2487-2498.

(The above trial compared early versus delayed initiation of ART in individuals with diagnosed cryptococcal meningitis and was stopped early, due to higher mortality in the early ART arm.)

Mollan, KR, Smurzynski, M, Eron, JJ. "Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide". Ann Intern Med. vol. 161. 2014. pp. 1-10.

(The above analysis showed a 2-fold higher risk of suicidality in those individuals who started a regimen with efavirenz for initial ART as opposed to those who started a regimen without efavirenz.)

Lennox, JL, Landovitz, RJ, Ribaudo, HJ. "Efficacy and tolerability of 3 nonnuceoside reverse transcriptase inhibitor-sparing regimens for treatment-naïve volunteers infected with HIV-1". Annals Intern Med. vol. 161. 2014. pp. 461-471.

(In this trial, three non-NNRTI initial ART regimens were compared for tolerability and virological efficacy; raltegravir performed the best in this trial, primarily due to tolerability.)

Raffi, F, Rachlis, A, Stellbrink, HJ. "Once-daily dolutegravir versus raltegravir in antiretroviral-naïve adults with HIV-1 infection: 48 week results from the randomized, double-blind, non-inferiority SPRING-2 study". Lancet. vol. 381. 2013. pp. 735-743.

Walmsley, S, Antela, A, Clumeck, N. "Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection". NEJM. vol. 369. 2013. pp. 1807-1818.

Clotet, B, Feinberg, J, van Lunzen, J. "Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naïve adults with HIV-1 infection (FLAMINGO): 48 week results from the randomized open-label phase 3b study". The Lancet. vol. 383. 2014. pp. 2222-2231.

(These three clinical trials summarize data for dolutegravir as initial therapy for HIV-1, as compared to other first line agents such as raltegravir, efavirenz, and boosted darunavir; results demonstrate non-inferior virological efficacy as compared to raltegravir and superior efficacy as compared to efavirenz and boosted darunavir, with superiority driven largely by tolerability.)

Sax, PE, Wohl, D, Yin, MT. "Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials". Lancet. vol. 385. 2015. pp. 2606-15.

Mills, A, Arribas, JR, Andrade-Villanueva, J. "Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3 non-inferiority study". Lancet Infect Dis. vol. 16. 2016. pp. 43-52.

Gallant, JE, Daar, ES, Raffi, F. "Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically-suppressed adults: a randomised, double-blind, active-controlled phase 3 trial". Lancet HIV. vol. 3. 2016. pp. e158-65.

Pozniak, A, Arribas, JR, Gathe, J. "Switching to tenofovir alafenamide, coforumulated with elvitegravir, cobicistat, and emtricitabine, in HIV-1 infected patients with renal impairment: 48-week results from a single-arm, multicenter, open-label phase 3 study". J Acquir Immune Defic Syndr. vol. 71. 2016. pp. 530-7.

Gallant, J, Brunetta, J, Crofoot, G. "Efficacy and safety of switching to a single-tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in HIV-1/hepatitis B coinfected adults". J Acquir Immune Defic Syndr. 2016 May 11.

(The above five clinical trials summarize data for tenofovir alafenamide [TAF], including virologic efficacy and safety, as compared to TDF as part of a complete ART regimen for treatment-naïve individuals in the setting of initial therapy, switching therapy, switching therapy in the setting of mild-moderate renal impairment, or for treatment of HIV-hepatitis B coinfection; overall, the results suggest that TAF is as efficacious virologically as TDF for treatment of HIV or HIV-hepatitis B with lower rates of proximal tubule wasting and bone mineral density loss.)

Chow, EPF, Read, TRH, Chen, MY. "Routine CD4 cell count monitoring seldom contributes to clinical decision-making on antiretroviral therapy in virologically suppressed HIV-infected patients". HIV Medicine. 2014 Sep 18.

Girard, PM, Nelson, M, Mohammed, P. "Can we stop CD4+ testing in patients with HIV-RNA suppression on antiretroviral treatment". AIDS. vol. 27. 2013. pp. 2759-63.

(These two analyses suggest that once an HIV-infected individual has been suppressed on ART and has a robust CD4 count, ongoing CD4 count monitoring is not necessary and does not affect clinical decision making; this finding is now reflected in the treatment guidelines.)

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