In most urban clinical settings, clinicians providing HIV care practice in an environment where infectious disease specialists and pharmacists well-versed in the treatment of HIV disease are readily available. Additionally, a standard of care has been established based on the documented proficiency of the clinicians providing HIV care. This standard of care states that only those clinicians seeing 20 or more patients ongoing are considered to be experienced and proficient in providing HIV care.1 Nonetheless, PAs in many non-HIV clinical settings are confronted with patients at risk for exposure or already infected and must provide education about and medical care for HIV disease. Thus PAs are responsible for knowing the most current information on the treatment of HIV disease.
The US Department of Health and Human Services (DHHS) sets the standard of care in many areas of medicine in the United States. The CDC, one of the DHHS agencies, is responsible for maintaining the guidelines for the use of antiretroviral (ARV) agents in HIV-1-infected adults and adolescents. The December 2009 DHHS guidelines provide the most current evidence-based information.2 The literature evaluated and summarized in the guidelines is extensive and addresses multiple issues related to medication resistance, drug interactions, adverse reactions, and adherence to therapy. This review addresses only the following subjects: the timing of antiretroviral therapy, criteria for initiation of therapy, and new data on potential first-line options for antiretroviral therapy.
WHEN TO START THERAPY
One of the most difficult patient questions to answer is, “When should I start taking medication for HIV?” Clinicians should look to the DHHS guidelines to assist them in answering this question.
The members of the guidelines committee had extensive discussions on the optimal time to initiate antiretroviral therapy, and the final recommendation is to start therapy in anyone with a CD4+ T-cell count (CD4 count) between 350 and 500 cells/mm3. Although this recommendation is established, the committee members were split on how strong the recommendation should be; 55% strongly supported it and 45% moderately supported it. In addition, approximately one-half of the DHHS panel favored starting ARV therapy for patients with CD4 counts ≥500 cells/mm3.2
The baseline evaluation of a patient with newly diagnosed HIV infection is extensive and includes a complete medical history, physical examination, laboratory evaluation, and counseling regarding the implications of HIV infection.2 In addition to confirming the diagnosis with a repeat of HIV antibody screening, an HIV viral load, CD4 count, and T-lymphocyte differentiation must also be obtained. If the patient's viral load is at least 500 to 1,000 copies/mL, genotypic resistance testing is advised as well. Additionally, the patient must be screened for tuberculosis; hepatitis A, B, and C; syphilis; and many of the other sexually transmitted infections. HIV-infected women should have a Pap smear annually, and HIV-infected men who have sex with men (MSM) are advised to have anal Pap smear screening for abnormalities secondary to exposure and infection with the human papillomavirus (HPV). HIV-1-infected patients must also be screened for antibodies to those pathogens, such as Toxoplasma, that may emerge as opportunistic infections if the patient's CD4 count continues to decline to less than 100 cells/mm3.2
Adding to the complexity of care, the HIV-infected patient may present with multiple barriers to care and to the initiation and maintenance of treatment. These cofactors are often identified in the screening history and physical examination and may be related to a wide range of factors, including substance abuse, unstable housing and economic support, homelessness, mental illness, and medical comorbidities. Subsequently, adherence to antiretroviral therapy may be interrupted, creating additional complexities in the form of resistance to the most efficacious and least toxic ARV medication regimens available.3
Acceptance of and adherence to therapy are primary determinants of effective viral suppression.3 Thus, only after evaluation of the HIV-infected patient's medical, psychological, and social circumstances can a decision be made as to the appropriateness of initiating antiretroviral therapy. According to the DHHS guidelines, “Patients initiating antiretroviral therapy should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy based on clinical and/or psychosocial factors.”2
“The guidelines for initiating ARV treatment were based on several large studies suggesting a potential benefit to earlier treatment.”
The clinician might consider initiating ARV therapy regardless of CD4 count in several situations, including a history of an AIDS-defining illness, the presence of acute opportunistic infections, pregnancy, HIV-associated nephropathy, hepatitis B coinfection when hepatitis B treatment is indicated, a CD4 count that is declining at >100 cells/mm3 per year, or a high HIV-1 viral load.2 The DHHS guidelines also discuss other situations in which therapy might be considered, including in the setting of a serodiscordant relationship to try to reduce the risk of transmission.2 For PAs who do not practice in HIV specialties, time for this discussion and initiation of antiretroviral treatment may be limited; therefore, maintaining a referral network to an HIV specialist or HIV practice is essential.
The guidelines for initiating ARV treatment were based on several large cohort studies suggesting potential benefit of earlier treatment. The SMART (Strategies for Management of Antiretroviral Therapy) trial demonstrated that the subset of patients who were not receiving antiretroviral therapy at study entry and who were assigned to start therapy at CD4 counts >350 cells/mm3 were less likely to experience any opportunistic disease or serious non-AIDS events than patients who were randomized to defer therapy until their CD4 count dropped to less than 250 cells/mm3.4,5 Many HIV-infected patients may be motivated to start therapy based on the results of the SMART trial and similar studies. For those who choose not to initiate therapy, the clinician must remain alert to the increased risk of opportunistic infections and to the presentation of other serious non-AIDS events.
In the 1990s, the standard practice was to use viral load as the primary surrogate marker for when to initiate ARV therapy.6 Currently, however, viral load is used as the secondary marker combined with the CD4 count as the primary surrogate marker. The DHHS guidelines state that treatment may be offered to a patient with significant cofactors or comorbidities and also if the CD4 count has declined by more than 100 cells/mm3 per year. Treatment may also be recommended for patients in this CD4 cell band who have a viral load >100,000 copies/mL.2
Transmission of drug-resistant HIV strains is well-documented and is associated with suboptimal virologic response to initial antiretroviral therapy.7,8 Thus all patients initiating antiretroviral therapy should have resistance testing with a genotyping assay before selecting a medication regimen. The goal of ARV therapy is to achieve an undetectable viral load. Laboratory studies recommended before and during treatment are listed in Table 1.
- Pas are responsible for knowing the most current information on the treatment of HIV disease, even if they do not work in an AIDS practice.
- The December 2009 US Department of Health and Human Services antiretroviral (ARV) treatment guidelines provide the most current evidence-based information on the timing of ARV therapy, criteria for initiation of therapy, and new data on potential first-line options for antiretroviral therapy.
- Based on efficacy data, durability of viral suppression, tolerability and toxicity profiles, and ease of use, the guidelines cite four preferred combination regimens for initiating ARV therapy. all the preferred regimens include tenofovir/emtricitabine with a non-nucleoside reverse transcriptase inhibitor, a boosted protease inhibitor, or an integrase inhibitor.
THE DISADVANTAGES OF EARLY ARV THERAPY
Earlier initiation of antiretroviral therapy at higher CD4 counts (>500 cells/mm3) will increase the time on therapy and thereby also increase the potential for long-term toxicities. This perceived risk has been a rationale for the deferral of initiating HIV therapy. Although newer ARV regimens are generally better tolerated, more convenient, and more potent than older regimens, there are fewer longer term safety data for the newer agents.2
Use of antiretroviral drugs for many decades may produce as yet unknown complications.2 The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study found an increased incidence of cardiovascular disease associated with cumulative exposure to some drugs within the nucleoside reverse transcriptase inhibitor and protease inhibitor classes.9 Clinicians treating HIV patients are encouraged to consult the guidelines, which provide a comprehensive list of known antiretroviral-associated toxicities along with prevention and management strategies.
Additionally, very early initiation of ARV therapy in patients who are nonadherent increases the risk of drug resistance. Though the greater convenience and potency of the current antiretroviral regimens facilitate adherence, some asymptomatic patients may be less motivated to remain adherent to their therapy. Treatment adherence is key to viral suppression and should be stressed prior to initiation of therapy and during follow-up visits.2
FIRST-LINE HAART REGIMENS
Available drugs for the treatment of HIV disease belong to six different classes: nucleoside (nucleotide) reverse transcriptase (RT) inhibitors (N[t]RTIs, 8 agents), nonnucleoside RT inhibitors (NNRTIs, 4 agents), protease inhibitors (PIs, 10 agents), an integrase inhibitor (1 agent), a fusion inhibitor (1 agent), and a CCR5 inhibitor (1 agent).10 Some of these drugs are used minimally, and some are not recommended for the initiation of ARV therapy because of side-effect profiles, high pill burden and/or inconvenient administration schedules, and difficulty managing drug-drug interactions.
The N[t]RTis are considered to be the backbone of the current combinations of highly active antiretroviral therapy (HAART). The standard of care for HIV patients is to initiate therapy with a three (or more)-drug regimen, two of which are most commonly N[t]RTIs. The success of N[t]RTIs in HIV therapy is primarily a consequence of their unique pharmacology and their inhibition of HIV reverse transcription.11
Over the past 25 years following the introduction of zidovudine (Retrovir) as the first antiretroviral agent, research has shown that combining two N[t]RTIs with a protease inhibitor, a nonnucleoside reverse transcriptase inhibitor, or (more recently) an integrase inhibitor is essential to achieve viral suppression. The clinical development of fixed-dose N[t]RTI combination pills—such as zidovudine/lamivudine (Combivir), zidovudine/abacavir/lamivudine (Trizivir), abacavir/lamivudine (Epzicom), and tenofovir/emtricitabine (Truvada)—has been effective in reducing pill burden and thereby increasing adherence to therapy and subsequently enhancing viral suppression.11
The contribution of N[t]RTIs to HAART and effective long-term viral suppression is in part attributable to their synergistic effects when combined with other classes of antiretroviral medications. Moreover, the N[t]RTI's ability to accumulate in the intracellular space and maintain prolonged retention as an active metabolite has led to effective once-daily dosing. Certain drugs in this class thereby contribute to a level of “forgiveness” towards medication nonadherence and buffer the pharmacokinetic fluctuations in the therapeutic levels of other drugs used in HAART.12 This synergistic effect means that the N[t]RTIs will most likely remain as the mainstay of ARV therapy for both treatment-naive and experienced HIV-infected patients.
The N[t]RTI class now includes eight individual drugs, four NRTI fixed-dose combinations, and one single-pill antiretroviral regimen, tenofovir/emtricitabine (N[t]RTI) + efavirenz (NNRTI) (Atripla).
Choosing an NNRTI or PI is the next step, after the two N[t]RTIs have been selected. Since the discovery in the 1990s of nevirapine (Viramune), delavirdine (Rescriptor), and efavirenz (Sustiva)—the first-generation NNRTIs—this class of medications has shown significant virologic efficacy in patients with NNRTI HIV-1 susceptibility. The specificity of the NNRTIs for HIV-1 is a significant advantage of this class of drugs.10
Unfortunately, because of its hepatotoxicity, tendency to cause rash, and higher susceptibility to virologic failure, nevirapine is not a first-line choice in the developed world. Based on World Health Organization (WHO) guidelines, nevirapine is considered a viable choice for initiating HIV treatment in developing countries; and many African countries, as part of their prevention of mother-to-child transmission (PMTCT) component of HIV programs, have developed policies and guidelines for the administration of a single dose of nevirapine to the mother and her infant at delivery. Despite the development of resistance in the mother and the known efficacy and increasing use of combination antiretroviral therapy in PMTCT prophylaxis, the nevirapine-based intervention has remained the approach of choice in many resource-limited settings because a feasible and affordable alternative is currently lacking.13,14 Delavirdine is rarely used, in the United States or elsewhere, primarily because it is susceptible to viral mutations, making it suboptimal in a HAART regimen for viral suppression.10
“Before ritonavir boosting became available, the protease inhibitors were found to not durably suppress replication of the virus.”
Efavirenz, the primary first-generation NNRTI, is currently offered as its own formulation and also in the combination drug Atripla. This combination was the first one-pill/one-dose-per-day treatment offered to HIV-1 infected patients. It is now considered to be one of the four preferred regimens for initiation of treatment.
Disadvantages of efavirenz are its tendency to cause CNS toxicity and rash and the potential for viral resistance to develop because of the drug's decreased genetic barrier.10 The primary CNS symptoms reported by day 7 of use include vivid dreams, off-balance or unsteady walking, light-headedness or drowsiness, and a sense of vertigo. Some of these symptoms have been treated with antihistamines, anxiolytics, and antidepressants. The efavirenz rash is generally mild to moderate and easily treated with antihistamines or corticosteroids. The CNS symptoms and rash typically resolve within the first 4 weeks following treatment initiation, but if they persist or worsen, discontinuation and switching of the treatment regimen is recommended.11
Of the next generation of NNRTIs, etravirine (Intelence) has shown a much better resistance profile when compared to efavirenz and an increased genetic barrier to the development of resistance.10 To date, etravirine has been tested on treatment-experienced patients and therefore is not included in the four preferred first-line regimens.
A protease inhibitor or integrase inhibitor is also a preferred choice when initiating HAART. The first-generation protease inhibitors were found to have high antiviral efficacy but were problematic in their lower bioavailability, excessive pill burden, and—for some—high levels of GI toxicity.11 Additionally, before ritonavir boosting became available, the PIs were found to not durably suppress viral replication.15
The second-generation protease inhibitors boosted with ritonavir (Norvir) have significantly improved bioavailability and half-life, thereby enhancing viral suppression. The second-generation PIs include amprenavir (Agenerase), fosamprenavir (Lexiva), lopinavir (Kaletra), atazanavir (Reyataz), tipranavir (Aptivus), and darunavir (Prezista). High pill burden has been a limiting factor with amprenavir, as has an increased resistance profile when unboosted. Fosamprenavir has been found to cause significant diarrhea and to elevate fasting cholesterol and triglyceride levels, possibly not making it a first choice for treatment.11 Tipranavir and nonretonivir-boosted atazanvir have both been found to have a narrow index of viral efficacy, resulting in multiple PI-resistance mutations. Additionally, tipranavir carries an increased risk of hepatotoxicity.15
Ritonavir-boosted lopinavir has been well-established as efficacious when combined with two N[t]RTIs. It can be taken once or twice daily, thereby potentially reducing pill burden. With once-daily dosing, GI toxicity is increased; thus, the DHHS guidelines list this as an alternative first-line regimen.2
Ritonavir-boosted atazanvir as a once-daily PI in combination with a N[t]RTI backbone is considered superior to ritonavir-boosted lopinavir because of its durability in viral suppression and reduced adverse drug reactions.15 These advantages explain why it is included in the preferred first-line regimens as part of a combined formulation.
Darunavir was approved in 2006 as the ninth protease inhibitor.15 This agent has been found to inhibit mutation to drug-resistant strains; it displays high antiviral potency and has a comparatively limited adverse events profile. When compared to lopinavir/ritonavir once- and twice-daily dosing, darunavir/ritonavir once daily was found to cause fewer GI side effects and fewer lipid profile abnormalities.15 As a result, it too is included in the preferred first-line regimens.
A medication from the strand transfer inhibitors of HIV-1 integrase is the most recent antiviral agent to be added to the preferred first-line regimen. This first integrase inhibitor —raltegravir (Isentress)—has introduced a new era to antiviral therapy. Comparative studies have shown that in combination with two N[t]RTIs, raltegravir is as efficacious as efavirenz in a similarly combined regimen.16 Additionally, raltegravir has a significantly reduced side-effects profile when compared to the side-effects profile of efavirenz. Increases in cholesterol and triglyceride levels were identified in a regimen including tenofovir and emtricitabine with efavirenz. In the same regimen, raltegravir was found to have minimal effects.11
THE BOTTOM LINE
Based on efficacy data, durability of viral suppression, tolerability and toxicity profiles, and ease of use, the DHHS 2009 recommendations for first-line treatment cite four preferred combination regimens for initiating ARV therapy:
- Tenofovir/emtricitabine (N[t]RTIs) plus efavirenz (NNRTI)
- Tenofovir/emtricitabine plus atazanavir/ritonavir (boosted PI)
- Tenofovir/emtricitabine plus darunavir/ritonavir (boosted PI)
- Tenofovir/emtricitabine plus raltegravir (integrase inhibitor).
All the preferred regimens include the N[t]RTIs tenofovir/ emtricitabine combined with an NNRTI, a boosted PI (protease inhibitor combined with a low-dose retonavir), or the integrase inhibitor, and there are several alternative regimens.2
Although this article provides a detailed review of the DHHS guidelines for the initiation of antiretroviral therapy in the HIV-infected patient, PAs caring for this patient population are strongly encouraged to obtain, review, and implement the full guidelines in their daily practice in order to follow the current standard of care.
1. Landon BE, Wilson IB, McInnes K, et al. Physician specialization and the quality of care for human immunodeficiency virus infection. Arch Intern Med.
2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2009; 1-161. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
. Accessed January 10, 2011.
3. Friedland GH. HIV medication adherence: the intersection of biomedical, behavioral and social science research and clinical practice. J Acquir Immune Defic Syndr.
4. Buchbinder SP, Jain V. Early versus deferred antiretroviral therapy for HIV. N Engl J Med.
2009; 361(8):822; author reply 823-824.
5. Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. Strategies for Management of Antiretroviral Therapy (SMART) Study Group. J Infect Dis.
6. Mellors JW, Rinaldo CR, Gupta P, et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science.
7. Little SJ, Holte S, Routy JP, et al. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med.
8. Borroto-Esoda K, Waters JM, Bae AS, et al. Baseline genotype as a predictor of virological failure to emtricitabine or stavudine in combination with didanosine and efavirenz. AIDS Res Hum Retroviruses.
9. The DAD Study Group. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med.
10. de Bethune MP. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009). Antiviral Res.
11. Hawkins T. Understanding and managing the adverse effects of antiretroviral therapy. Antiviral Res.
12. CihlarT, Ray AS. Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res.
13. Fowler MG, Mofenson L, McConnell M. The interface of perinatal HIV prevention, antiretroviral drug resistance, and antiretroviral treatment: what do we really know? J Acquir Immune Defic Syndr.
14. Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS.
15. Wensing MJ, vanMaarseveen NM, Nijhuis M. Fifteen years of HIV protease inhibitors: raising the barrier of resistance. Antiviral Res.
16. McColl D, Chen X. Strand transfer inhibitors of HIV-1 integrase: bringing in a new era of antiretroviral therapy. Antiviral Res.
EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 46 and successfully completing the posttest on page 51. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of February 2011.