The introduction of highly active antiretroviral therapy (HAART) has revolutionized the treatment and management of patients with HIV infection. Treatment with such regimens has led to sustained suppression of viral replication, partial restoration of immune function, and a decrease in HIV-related morbidity and mortality .
With the numbers of new drugs and drug classes increasing steadily, the choice of potential first-line antiretroviral (ARV) agents is at unprecedented levels . Initiating therapy in the treatment-naïve patient is no longer only about prolonging life, but is also about ensuring good quality of life, through potent, tolerable, and convenient ARV regimens . Given the choices of drugs available, treatment guidelines for starting therapy in treatment-naïve patients must consider several patient-related and therapy-related factors when making recommendations to physicians. In this study, we review the current status of ARV combination therapy in treatment-naïve patients.
Considerations for starting antiretroviral therapy in treatment-naïve patients with HIV infection
The primary goal of ARV therapy is to reduce HIV-associated morbidity and mortality. Research has shown this to be best achieved through the use of ARV combination therapy, such as the preferred regimens in most current ARV guidelines, to maximally inhibit HIV replication . However, before selection of an initial HAART regimen, clinicians must make several decisions based on various factors. The first, and perhaps most important of these, is deciding when to start treatment .
When to start treatment
The guidelines of several organizations [including the European AIDS Clinical Society (EACS) , US Department of Health and Human Services (DHHS) , and WHO ] generally recommend the initiation of ARV therapy in treatment-naïve HIV-infected patients with a CD4+ cell count greater than or equal to 350 cells/μL, regardless of their status as symptomatic or asymptomatic [2–5]. Of note, after more recent debate, the recommended CD4+ threshold has been increased to 500 cells/μL . Furthermore, several characteristics, such as the presence of barriers to adherence and comorbidities, may preclude ARV treatment initiation, independent of CD4+ cell count .
The EACS guidelines, in particular, recognize the importance of symptom status regarding the timing of treatment initiation. These guidelines recommend immediate initiation of treatment in symptomatic patients with a CD4+ count greater than 200 cells/μL, in patients with opportunistic infections, or in symptomatic patients with Centers of Disease Control stage 3 disease . In asymptomatic patients, treatment is recommended without delay for those with a CD4+ count less than 350 cells/μL, and is recommended in patients with a CD4+ count of 350–500 cells/μL in the following subgroups: patients with hepatitis B/C coinfection, malignancy, or an HIV-associated organ deficiency (e.g., nephropathy); patients aged older than 50 years; and patients who are pregnant .
Factors to consider when selecting an initial regimen
Selection of an initial HAART regimen should be individualized for each specific patient and should be based on several patient-related and drug-related factors [2,3].
Factors to consider when starting ARV therapy in treatment-naïve patients are as follows: [2,3]
Crucially, to begin ARV therapy, the patient must be ready, able and willing to adhere to lifelong treatment. Adherence to treatment is essential to achieve sustained virologic suppression and prevent the emergence of resistance .
The 2011 treatment guidelines for use of ARV agents in HIV-1 infected adults and adolescents  provide guidance on the use of laboratory tests for initial and ongoing assessment of HIV-1 patients to determine the virologic and immunologic efficacy of HAART. The primary surrogate markers of clinical efficacy are CD4+ count to determine immune function, and plasma HIV RNA level (viral load) to indicate response to HAART. Together with genotypic resistance testing, or human leukocyte antigen (HLA) B*5701 testing before starting abacavir, these assays guide initial selection and ongoing modification of HAART to enable an optimal response to be achieved for an individual patient. In the case of lack of response/treatment failure, genotypic and phenotypic resistance testing can be performed. In addition, a coreceptor tropism assay should be performed before, or on, virologic failure of a chemokine coreceptor antagonist therapy [i.e., maraviroc] .
Although certain characteristics influence ARV combination therapy choice in all patients, importantly, patients with severe symptomatic disease may face more restrictions and so have fewer therapeutic options available .
Current treatment guidelines
Various drug classes are currently recommended and used as first-line treatment options for patients with HIV infection . These include nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs; with or without ritonavir boosting [/r]), and integrase strand transfer inhibitors (INSTIs). Some guidelines also recommend a chemokine coreceptor antagonist as an alternative. In general, guidelines worldwide recommend the use of a dual NRTI combination ‘backbone’, along with one of the following: an NNRTI, a ritonavir-boosted PI (PI/r), or an INSTI [2–4].
The current April 2011 EACS guidelines recommend initiation of first-line treatment with two NRTIs in combination with an NNRTI, PI/r, or INSTI (Table 1) . The January 2011 revised DHHS guidelines recommend first-line treatment with one of the following: efavirenz/tenofovir disoproxil fumarate (tenofovir DF)/emtricitabine (Atripla®); or a combination of either a PI/r [atazanavir/r or darunavir/r] or INSTI [raltegravir], along with the fixed-dose combination tenofovir DF/emtricitabine (Truvada®) . The WHO guidelines recommend only the use of an NNRTI along with a dual NRTI combination as a first-line treatment option .
Fixed-dose NRTI combinations that are widely recommended as components of first-line treatment for patients with HIV infection are tenofovir DF/emtricitabine and abacavir/lamivudine (Kivexa®/Epzicom®) [2–4]. Other NRTI-based ARV regimens include zidovudine/lamivudine and didanosine/lamivudine or emtricitabine , although these are only recommended in resource-poor settings in the WHO guidelines .
The two NNRTIs traditionally recommended for inclusion in a first-line HAART regimen are efavirenz and nevirapine [2,3]; in the DHHS US guidelines, efavirenz is the preferred NNRTI , whereas the EACS does not distinguish between these two NNRTIs . EACS guidelines recommend the use of one of four PIs in a first-line regimen, and two as alternative options (Table 1) . However, DHHS guidelines list only two recommended ritonavir-boosted-PI regimens (atazanavir/r and darunavir/r), and leave lopinavir/ritonavir (lopinavir/r) and fosamprenavir/ritonavir (fosamprenavir/r) as alternatives, except in pregnancy, where lopinavir/r is preferred . Both guidelines also recommend raltegravir as a preferred first-line regimen component [2,3].
Comparisons of first-line antiretrovirals
Within the framework provided by the various guidelines described earlier, there are several important considerations when choosing an initial HAART regimen.
Antiretroviral therapy-specific considerations
Traditionally, ARV combinations were classified according to the use of NNRTIs or PIs; however, with the emergence of new ARV classes, this concept may change. New efficacy concepts, such as the infectivity index proposed by Siliciano , and new insights into HIV pathology, such as immune activation driven by bowel epithelial and gut-associated lymphoid tissue disruption and Th17 T-cell depletion [6,7], may lead to changes in therapies for HIV infection. Research suggests that depletion of Th17 cells, for example, may be critical in determining the pace of HIV disease progression , and may become a key target for development of novel therapeutic regimens, such as IL-7, that minimize or ameliorate damage to the gastrointestinal tract . Also, the immune activation driven by microbial translocation in the gut might be a new target of HIV non-ARV therapy .
The management and avoidance of drug toxicity is another important consideration. Long-term toxicity knowledge remains dependent upon insights from clinical practice and limited evidence from long-term patient cohorts [9,10•]. Moreover, this evidence is stronger for older drugs; for new drugs and drug classes, such as INSTI or CC-chemokine receptor 5 (CCR5) antagonists, such evidence is lacking. Class-sparing regimens may eventually provide benefit to specific patient populations .
Some hypersensitivity reactions are now preventable with genetic testing; in the near future, with more tests, ARV agent administration may be safer .
When proposing equally potent regimens, convenience and tolerability are the most important issues to discuss with the patient. Truly once-daily regimens are the preferred choice, as they may promote adherence, a major driver of therapeutic success .
Importantly, data from clinical trials must be compared with caution, as methodologies and populations may differ widely between trials. Any conclusions drawn from trials must refer to the regimen tested, and not to one or some of the individual agents used in the regimens.
Comparisons of nucleoside reverse transcriptase inhibitors
For toxicity and simplicity reasons, the first-choice NRTI backbone has been skewed towards two fixed-dose combinations: tenofovir DF/emtricitabine (Truvada®) and ABC/3TC (Kivexa®/Epzicom®); both combinations are administered as one pill once-daily. The main toxicity concerns associated with tenofovir DF are renal proximal tubule dysfunction and subsequent phosphate depletion, with a possible increased incidence of renal failure; loss of bone mineral density is also a concern with long-term tenofovir DF treatment . abacavir use is associated with a well established hypersensitivity reaction in patients carrying the HLA B*5701 haplotype, and a considerable debate continues concerning possible increased cardiovascular risk, namely acute myocardial infarction, in patients with traditional cardiovascular risk factors [10•,13]. A new meta-analysis, sponsored by the FDA, showed no association of abacavir with acute myocardial infarction ; however, randomized, prospective studies are required to investigate this issue further. Thus, it seems wise, based on currently available data, to restrict abacavir use to patients with low cardiovascular risk. abacavir/lamivudine also proved inferior to tenofovir DF/emtricitabine in patients with a viral load greater than 100 000 copies/mL in the AIDS Clinical Trial Group (ACTG) 5202 trial , so use of abacavir/lamivudine should also be restricted in this situation.
Nonnucleoside reverse transcriptase inhibitors vs. protease inhibitors
It is a widely held belief that boosted PIs are more potent reducers of viral load than other ARVs, but no clinical trials to date have clearly demonstrated this. Indeed, efavirenz hegemony might be challenged by a new NNRTI, rilpivirine (TMC-278). Rilpivirine was noninferior to efavirenz in an intent-to-treat (ITT) time-to-loss of virologic response analysis of pooled 48-week data from the ECHO and THRIVE phase III studies . However, questions remain to be answered about the higher number of virologic failures in the rilpivirine group, especially in patients with higher baseline viral loads (100 000 copies/mL) . The added value of rilpivirine is that it was better tolerated than efavirenz, with fewer CNS-related adverse events and fewer grade 3/4 lipid abnormalities . In the ECHO study, there was also a lower risk of vitamin D deficiency with rilpivirine vs. efavirenz . A co-formulation of rilpivirine along with tenofovir DF/emtricitabine is in development and will soon be filed for regulatory approval; approval of this co-formulation will increase the number of single-pill treatment options available to patients.
Presently, four other major trials have attempted to clarify the PI vs. NNRTI debate: ACTG 5142 (lopinavir/r vs. efavirenz), ARTEN (atazanavir/r vs. nevirapine), ALTAIR (atazanavir/r vs. efavirenz), and ACTG5202 (atazanavir/r vs. efavirenz) [15,18–20].
In ACTG 5142, efavirenz combined with different nucleoside backbones showed virologic superiority over LPV/r (along with a nucleoside backbone) in the ITT population; on the other hand, lopinavir/r showed superiority in terms of CD4+ cell count recovery at week 96 . The ARTEN  and ALTAIR  trials demonstrated noninferiority of nevirapine and efavirenz, respectively, when used in combination with a tenofovir DF/emtricitabine backbone, compared with therapy with atazanavir/r.
The ACTG 5202 trial compared the two most frequently used NRTI combinations, abacavir/lamivudine and tenofovir DF/emtricitabine, each in combination with efavirenz or atazanavir/r. At week 96, atazanavir/r demonstrated noninferiority to efavirenz. There were differences in the safety of these combinations, as an inferior time to adverse events was observed with abacavir/lamivudine along with efavirenz . Furthermore, the antiviral efficacy of abacavir/lamivudine was inferior to tenofovir DF/emtricitabine when baseline viral load was greater than 100 000 copies/mL .
Comparisons of nonnucleoside reverse transcriptase inhibitors with new antiretroviral drug classes
As efavirenz is established as a cornerstone of HIV therapy in treatment-naïve patients, the drug was used as a comparator in two recent randomized trials of new ARV drug classes. The STARTMRK trial compared raltegravir with efavirenz (both in combination with tenofovir DF/emtricitabine). The raltegravir-based regimen demonstrated noninferiority to efavirenz, with a faster time to confirmed virologic response and fewer CNS adverse effects .
The CCR5 HIV entry inhibitor maraviroc was compared with efavirenz [both in combination with zidovudine/lamivudine (Combivir®)] in the Maraviroc vs. Efavirenz Regimens as Initial Therapy (MERIT) study [22,23]. The first analysis failed to show noninferiority of maraviroc to efavirenz, but a re-analysis with a more sensitive tropism assay demonstrated noninferiority . Furthermore, the safety profile of maraviroc over 96 weeks was good, with no increase in malignancies compared with efavirenz, and with a better lipid profile than efavirenz .
With the development of new, specific ARV drug classes, precise patient selection is of vital importance if patients are to derive benefit from treatment. Of note, a large phase III study (NCT01095796 ) is currently investigating the safety and efficacy of a single-tablet regimen (QUAD) containing fixed doses of a new INSTI, elvitegravir (boosted with cobicistat), in combination with tenofovir DF and emtricitabine, compared with efavirenz/tenofovir DF/emtricitabine (Atripla®). Another phase III trial of the QUAD regimen is also underway (NCT01106586) .
Comparisons of protease inhibitors
Boosting systemic exposure to various PIs with ritonavir remains the mainstay of PI therapy due to concerns about treatment resistance with unboosted PIs and patient convenience. However, the ARIES trial recently showed that after 6 months of boosted therapy, unboosted atazanavir combined with abacavir along with lamivudine was as effective as atazanavir/r in combination with abacavir along with lamivudine in controlling viral load, and was also associated with a better lipid profile [26•].
lopinavir/r (Kaletra®) has been the boosted PI of choice for many years as it remains the only co-formulated boosted PI available. However, toxicity concerns, mainly due to the ritonavir component, have led to the search for less toxic alternatives. Two trials of newer boosted-PI based regimens have recently demonstrated efficacy at least as good as or better than that of lopinavir/r [27,28]. In the CASTLE trial, once-daily atazanavir/r was noninferior to twice-daily lopinavir/r at the 96-week ITT analysis; atazanavir/r was associated with less toxicity than the lopinavir/r regimen . In the ARTEMIS trial, once-daily darunavir/r demonstrated superiority over lopinavir/r in the 96-week ITT analysis, and had a better gastrointestinal and lipid profile .
In both trials, the efficacy of lopinavir/r was dependent upon CD4+ cell strata: there was a reduction in efficacy for CD4+ counts less than 200 cells/μL in the ARTEMIS trial , and for less than 100 cells/μL in CASTLE . However, these were posthoc analyses, and the studies were not powered to evaluate such strata.
The KLEAN study, which compared twice-daily fosamprenavir/r with lopinavir/r, failed to show any advantage in terms of toxicity . The GEMINI study, comparing twice-daily ritonavir-boosted saquinavir with lopinavir/r, demonstrated similar efficacy for the two regimens, with only slightly less metabolic toxicity associated with saquinavir/r .
Currently, only one alternative booster agent to ritonavir is undergoing clinical development. Gilead's cobicistat is being compared with ritonavir as a booster for atazanavir in a phase II trial (NCT00892437) , and in a new, large phase III trial (NCT01108510) . Preliminary data indicated potential kidney toxicity with cobicistat . However, results from another phase II trial of a cobicistat-boosted elvitegravir-based regimen (but vs. a different comparator regimen than the previously mentioned trials) reported that none of the patients in the cobicistat treatment arm (or the comparator arm) discontinued treatment due to changes in serum creatinine or estimated glomerular filtration rate .
Several PIs are being used in class-sparing regimens in association with either raltegravir (atazanavir , lopinavir , darunavir ) or reduced-dose maraviroc (atazanavir/r + maraviroc 150 mg once daily)  in treatment-naïve patients. Of these trials, only one did not use a ritonavir booster: the SPARTAN study, which found that the antiviral efficacy at week 24 of atazanavir along with raltegravir was consistent with atazanavir/r along with tenofovir DF/emtricitabine . Grade 4 hyperbilirubinemia was reported in 20.6% (13/63) of patients in the experimental group, but in none of the patients in the atazanavir/r along with tenofovir DF/emtricitabine group, and 6.3% of patients in the experimental group developed resistance to raltegravir. Consequently the SPARTAN study was discontinued. In the PROGRESS study, the antiviral efficacy of lopinavir/r along with raltegravir was noninferior to that of lopinavir/r along with tenofovir DF/emtricitabine . Further support for an NRTI-sparing regimen comes from another pilot study (A4001078), where there was similar antiviral efficacy between the atazanavir/r along with maraviroc and the atazanavir/r along with tenofovir DF/emtricitabine groups (proportion of patients with HIV-1 RNA of less than 50 copies/mL: 80.0% vs. 88.5%) . Grade 3 or 4 hyperbilirubinemia occurred in 16 maraviroc recipients vs. 8 tenofovir DF/emtricitabine recipients.
On the basis of these findings, a new phase III trial was initiated (and is currently enrolling patients); this study will investigate maraviroc in combination with darunavir/r instead of atazanavir/r. Unlike study A4001078, there was an unexpectedly high rate of virologic failure in the NRTI-free darunavir/r along with raltegravir treatment group in the ACTG A5262 study, particularly in patients with a high viral load at baseline . The rate of virologic failure was 15% at week 24, and 26% at week 48. The reasons for these unexpected results are not known. Further investigation of NRTI-sparing regimens is required. Notably, newer trials have also demonstrated that PI monotherapy (darunavir/r), after an induction phase of classical HAART, may be a safe and effective option for some treatment-naïve patients .
Drug resistance profile in treatment-naïve patients
Transmitted drug resistance
Transmitted drug resistance (TDR), or primary HIV-1 resistance, is well documented . The incidence of TDR has increased over time, with US  and UK  reporting the highest prevalence. Recently, however, reports have indicated that transmission of viral strains with drug resistance mutations has stabilized  or even decreased . The cause of the latter trend is not entirely clear, although the increasing efficacy of ARV therapy, combined with a larger number of patients reaching and maintaining an undetectable viral load for sustained periods – thus selecting less drug resistance and lowering HIV transmission – is likely to be part of the answer. Another possible explanation is linked to the increasing numbers of new infections detected in immigrant populations originating from countries where access to ARV therapy is limited or even absent .
To date, all large studies of TDR were performed by sequencing HIV-1 protease and part of HIV-1 reverse transcriptase through population sequencing. The sensitivity of this method for minority populations in the viral quasispecies is low. Other studies, using different methods that permit the detection of resistance mutations in minority viral populations, reported drug resistance mutations in these minority variants and demonstrated an association between the mutations and reduced treatment efficacy .
Thus, studies relying on population sequencing underestimate the real incidence of TDR. It is therefore generally recommended that a first-line regimen for a patient infected with a resistant virus must have a high genetic barrier to resistance – meaning, in practical terms, a boosted PI-based regimen.
In Portugal, there are no surveillance systems for reporting TDR. Only one prospective controlled study has been conducted to date, and this was part of a large, European, multicenter study . This study evaluated the prevalence of TDR in 2003 and 2005, in a population of 324 newly diagnosed patients [46,47]. In 2003, the incidence of TDR was 7.8%, and, in 2005, 8.3%. It appears that TDR has stabilized in Portugal, although these results should be confirmed in a more recent study and with a larger sample size. Another study of TDR in treatment-naïve patients (n = 2793) mainly from European countries (20 European countries along with Israel) analyzed trends between September 2002 and December 2005 . A sharp decrease in resistance to PIs (P = 0.04), a moderate decrease in resistance to NRTIs (not significant), and a decrease in resistance to NNRTIs after an initial increase (P = 0.02) was found. More recent data are required to confirm whether these trends have remained the same in the period since these studies were conducted.
TDR has an impact on public health, particularly in areas such as disease prevention. Thus, continued recommendations for resistance testing and for the choice of a first-line treatment regimen are needed. A surveillance programme must be implemented to allow informed decisions on such matters.
Acquired drug resistance
Acquired drug resistance occurs as a direct result of treatment with ARV agents, and is one of the causes of treatment failure – particularly in patients who experience multiple treatment failures . Acquired drug resistance to ARV therapy is far more common than TDR. However, prevalence data are often unclear due to differing methodologies and changes in drug resistance testing over time . A recent 10-year longitudinal study from the Swiss HIV Cohort Study found that the prevalence of drug-resistant virus in ARV-exposed patients was approximately 50–60% in 1999 and 39–53% in 2006 .
Virologic failure may result in the emergence and accumulation of additional resistance mutations. This is especially applicable to ARVs with a low genetic barrier to resistance, such as the NNRTIs, INSTIs, and some NRTIs . Selection of a single mutation generally leads to the development of high-level resistance against NNRTIs, and resistance also tends to occur quickly after treatment failure. The potential for cross-resistance in this drug class is also well documented . The same low genetic barrier and high potential for cross-resistance has been demonstrated with the NRTIs lamivudine and emtricitabine .
Genetic barrier of ritonavir-boosted protease inhibitors
Ritonavir-boosted PIs offer a higher genetic barrier to resistance than other drug classes such as NNRTIs and NRTIs. Thus, clinical resistance to ritonavir-boosted PIs is usually a more gradual process requiring the acquisition of several mutations [48,52].
Results from patients in the 10-year Swiss HIV Cohort Study showed that, of the 489 patients who started combination ARV therapy with a PI, PI/r, or NNRTI, mutations conferring resistance to individual drugs in the treatment regimen were found in 84%, 30%, and 66%, respectively, of patients who experienced a first-line virologic failure and for whom test results were available (n = 142) . Patients in the unboosted PI and NNRTI groups acquired a median of two mutations during treatment, compared with a median of zero mutations in the boosted PI group (P < 0.001) . Class cross-resistance was also observed more frequently in the NNRTI group (50%) than in the unboosted (17%) or boosted PI groups (10%; P < 0.001) .
Backbone regimen protection by protease inhibitors
The higher genetic barrier to resistance observed with boosted PIs is also associated with lower frequencies of NRTI resistance at the time of virologic failure. This ‘protection’ of the HAART backbone regimen has been demonstrated in clinical studies (Fig. 1) [54,55]. A double-blind trial compared the safety and efficacy of lopinavir/r with nelfinavir [both in combination with open-label stavudine and lamivudine] in 653 treatment-naïve patients . In patients with HIV RNA levels greater than 400 copies/mL at any point during the 48-week trial, resistance to lamivudine was less frequent in lopinavir/r-treated patients than nelfinavir recipients (41% vs. 82%, P < 0.001) . An analysis of long-term data, in patients who had a least one HIV RNA value greater than 400 copies/mL from week 24–108, confirmed these results (Fig. 1) .
There are several significant considerations when selecting an initial ARV regimen for a treatment-naïve patient: the patient's readiness to begin treatment is one of the most important considerations. Current European and US guidelines are in broad agreement regarding first-line treatment options: both guidelines currently recommend the use of either NNRTI-based or PI/r-based regimens, all of which show good antiviral efficacy and tolerability. However, certain NNRTIs and INSTIs may have a low genetic barrier to resistance and, with the growing issue of TDR, a PI-based regimen, with its higher genetic barrier and lower frequency of cross resistance, may be a better option in selected patients. If a resistance test is performed before starting treatment, and no evidence of NNRTI resistance is found, then an NNRTI may be selected as a component of the treatment regimen. Integrase inhibitor-resistance testing is not currently recommended, as there are no reported cases of transmission of INSTI resistance. Notably, the concept of a genetic barrier to resistance is only important in the case of TDR detected by a resistance test.
The choice of available first-line ARV agents is at unprecedented levels. Physicians and patients are able to choose from multiple agents with generally good tolerability, acceptable toxicity, and excellent antiviral efficacy. Thus, each regimen should be individualized to a patient's particular needs to provide the most effective, tolerable, and long-lasting treatment option.
Authors would like to thank Caroline M. Perry, Tracy Harrison, and Mary Hines of inScience Communications, a Wolters Kluwer business, for their medical writing support.
Conflicts of interest
Ricardo Camacho has received fees for consultancies from Boehringer-Ingelheim, grants from Merck Sharp & Dohme and ViiV Healthcare, payment for lectures from Abbott Laboratories, Boehringer-Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Roche and ViiV Healthcare as well as payment for the development of educational presentations from Gilead Sciences, GlaxoSmithKline and ViiV Healthcare. Eugénio Teófilo has received fees for consultancies from Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme and Pfizer, as well as payment for lectures from Bristol Myers Squibb, Merck Sharp & Dohme and ViiV Healthcare.
Funding for the preparation of this publication was provided by Janssen-Cilag, Portugal.
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