Initiation of antiretroviral therapy in the treatment-naïve patient

Mark Bloch : Holdsworth House Medical Practice and East Sydney Doctors, Sydney NSW
Craig Rodgers : Addiction Medicine Specialist, St Vincent’s Hospital, Sydney NSW

Initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) in the naïve patient centres around two main questions: When to start therapy and what to therapy to start. Data from recently published studies have provided evidence supporting starting therapy as soon after diagnosis as possible.[1][2] The standard use of a three-drug regimen consisting of an anchor drug with a backbone of two nucleoside analogue drugs remains the recommendation for therapy. The addition of newer drugs, particularly from the integrase strand transfer inhibitor (INSTI) class, with beneficial efficacy and tolerability, has changed the choice of the anchor drug used to commence therapy.[3][4][5] Because the key determinant of treatment success involves a commitment by the patient to ongoing treatment adherence, the critical decision to initiate ART is the patient’s readiness and willingness to commence treatment.[6]

The current gold standard of triple combination antiretroviral therapy (cART, previously referred to as highly active antiretroviral therapy or HAART) has evolved in the context of significant advances in the understanding of viral dynamics[7] and HIV drug resistance. Early trials of monotherapy with zidovudine demonstrated limited clinical benefit and virological and immunological failure, now known to be due in part to the development of drug resistance. Studies of dual nucleoside reverse transcriptase inhibitors or nucleoside analogues (NRTIs) published in 1996-1997 showed improved survival in asymptomatic individuals.[8][9] Shortly after, the early studies of triple therapy with two NRTIs and a protease inhibitor (PI) demonstrated a reduction in morbidity and mortality in individuals with advanced HIV.[10]

Due to the existence of a latently infected pool of long-living CD4 cells (established early in HIV infection),[11] currently available ART is unable to achieve eradication of HIV infection. The current goals of therapy are:

  • attaining maximal and durable suppression of HIV replication (as measured by a viral load below the limit of detection) with a well tolerated and simplified cART regimen
  • restoring and preserving immune function
  • reducing HIV-related morbidity
  • reducing non-acquired immune deficiency syndrome (AIDS) comorbidities
  • improving both quality of life and survival
  • preventing HIV transmission. 

As newer agents with simpler dosing schedules (including fixed-dose combinations) and more favourable toxicity profiles have become available, there has been a shift in emphasis towards early recognition and minimisation of treatment-related toxicities and early intervention with strategies to improve adherence, in order to achieve a durable treatment response.

In addressing the questions faced by individuals living with HIV and their clinicians – when to start therapy and which regimen to choose – the discussion below outlines the current consensus approach in Australia which is based on a mix of available clinical trial data and expert opinion.[12] The Australian commentary[13] on the US Department of Health and Human Services (DHHS) antiretroviral guidelines[14] are reviewed regularly in parallel with the review of the DHHS guidelines, and the most recent iteration may be found on the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) website.

When to start therapy in the individual with HIV

In the Australian context, ASHM Sub-Committee for Guidance on HIV Management recommends that antiretroviral therapy should be initiated in all people with HIV, irrespective of CD4 count, taking into account the following principles:[15]

  1. ART is recommended for all individuals with HIV infection, irrespective of CD4 count, to reduce the risk of disease progression.
  2. The decision to start ART should take into account both personal health benefits and risks, and reduction in transmission risk.
  3. Clinicians should regularly discuss the current state of knowledge regarding when to start ART with all individuals with HIV who are not yet on treatment.
  4. All decisions to start ART should be made by the individual with HIV, in consultation with their health-care providers and on the basis that they are fully informed and supported in their decision making.

This recommendation is consistent with guidance from the US DHHS Panel, which has recently been upgraded to an A1 Recommendation (strong recommendation based on data from randomised controlled trials) following the publication of the results of the START[16] and TEMPRANO[17] trials, which showed benefit in initiating therapy in patients with normal immunity.

Treatment as prevention

Apart from the personal benefit in initiating ART to the individual, there is a benefit in prevention of transmission of HIV to partners without the infection where the person initiating ART achieves and maintains virological suppression on therapy.

Recent data from interim analyses of two cohort studies presented at Conference on Retroviruses and Opportunistic Infections (CROI) in 2014 and 2015 reported no transmissions in serodiscordant homosexual male couples with undetectable viral load. This result included data from the European PARTNER study[18] which reported no HIV transmissions in 308 couple-years of follow-up when condomless anal intercourse was reported, and the HIV-positive partner had undetectable viral load[19] and data from the Australian-Thai-Brazilian Opposites Attract study, which reported no transmissions when condomless anal intercourse was reported in 89 person-years of follow-up in couples with viral load less than 200 copies/mL.[20] Data from these two studies strongly suggest that ART greatly reduces HIV transmission in serodiscordant homosexual couples. A very low rate of transmission cannot be ruled out. Follow-up continues in both studies and final study results are expected in 2016-17.

Cohort and randomised clinical studies in the pre-cART era[21] and cART era[22] suggested an enormous benefit in terms of reduction in both mortality and progression to AIDS as a result of cART. These studies have been pivotal in the development of the HIV treatment guidelines.

The clear benefit to the individual of commencing cART irrespective of CD4 count has been demonstrated through the results of two major randomised studies, START and TEMPRANO. The benefit of early cART initiation in reducing HIV transmission has been demonstrated in the randomised HPTN 052 study.[23]

Patients with CD4 counts > 500 cells/μL

Results for two pivotal randomised controlled trials (START[24] and TEMPRANO[25]) were recently published, both demonstrating that the clinical benefits of ART are greater when ART is started early, with pre-treatment CD4 T-lymphocyte (CD4) counts > 500 cells/μL, than when initiated at a lower CD4 cell count threshold.

With the availability of the START and TEMPRANO trial results, the DHHS Panel’s overall recommendation remains the same: ART is recommended for all patients with HIV infection regardless of pre-treatment CD4 count. However, the strength of the recommendation will be changed to AIa (strong recommendation based on data from randomised controlled trials) for all patients.

The additional benefit of ART in reducing the risk of HIV transmission further underscores the potential public health value of this recommendation. The Panel continues to emphasise that patients starting ART should be willing and able to commit to treatment and to understand the benefits and risks of therapy and the importance of adherence. On a case-by-case basis, ART may be deferred because of clinical and psychosocial factors, but therapy should be initiated as soon as is feasible.

It should be noted that neither of these trials included adolescents. However, our recommendations have been extrapolated to adolescents based on the expectation that they will derive benefits from early ART similar to those observed in adults.

Below are summaries of the results from these two randomised controlled trials:

START (Strategic Timing of AntiRetroviral Treatment) trial[26]

The START trial is a large, multinational, randomised controlled clinical trial designed to evaluate the role of early ART in asymptomatic patients with HIV infection in reducing a composite clinical endpoint of AIDS-defining illnesses, serious non-AIDS events or death. In this study, ART-naive adults (aged >18 years) with HIV infection with CD4 counts > 500 cells/μL were randomised to either initiate ART immediately (early arm) or wait until CD4 counts declined to < 350 cells/μL or until the development of a clinical indication for therapy (deferred arm).

A total of 4,685 participants were enrolled in this study, with a mean follow-up of 3 years. In May 2015, interim study data reviewed by the study’s independent Data and Safety Monitoring Board (DSMB) showed a significantly greater number of clinical events in the deferred therapy arm than in the early therapy arm. On the basis of these interim results, the DSMB concluded that the data provided significant evidence of the benefit of early ART and recommended that the study sponsor make the results available to the public and offer treatment to any study participants in the deferred therapy arm not yet on ART. The study participants will continue to be followed in this study until the end of 2016.

When the randomised arms of the study were closed, the primary endpoint of serious AIDS or non-AIDS events was reported in 42 participants (1.8%, or 0.60 events/100 person-years) in the early ART arm and 96 participants (4.1%, or 1.38 events/100 person-years) in the deferred ART arm (hazard ratio, 0.43, favouring early ART [95% confidence interval (CI), 0.30–0.62, p < 0.001]). The most common clinical events reported were tuberculosis and AIDS and non-AIDS malignancies.

TEMPRANO ANRS 12136 study[27]

The TEMPRANO study is a randomised controlled trial conducted in Cote d’Ivoire. Using a two-by-two (2 X 2) factorial design, participants with HIV infection with CD4 counts < 800 cells/μL were randomised to either immediate ART or deferred ART (based on the national guidelines criteria for starting treatment) and with or without isoniazid for prevention of tuberculosis for 6 months. The primary study endpoint was a combination of all-cause deaths, AIDS diseases, non-AIDS malignancies, and non-AIDS invasive bacterial diseases. More than 2,000 participants enrolled in the trial, with a median follow-up of 30 months. Among the participants, 849 had baseline CD4 counts > 500 cells/μL. In the analysis of this high CD4 count subgroup, 68 primary outcome events were reported in 61 patients. The risk of primary events was lower with immediate ART than with deferred ART, with a hazard ratio of 0.56 in favour of early ART (CI, 0.33–0.94). On the basis of these results, the study team concluded that early ART is beneficial in reducing the number of these clinical events.

Prevention of sexual transmission

A number of investigations, including biological, ecological and epidemiological studies and one randomised clinical trial, provides strong support for the premise that treatment of the individual with HIV can significantly reduce sexual transmission of HIV. Lower plasma HIV RNA levels are associated with decreases in the concentration of the virus in genital secretions.[28][29] Studies of HIV-serodiscordant heterosexual couples have demonstrated a relationship between level of plasma viraemia and risk of transmission of HIV—when plasma HIV RNA levels are lower, transmission events are less common.[30][31][32] A study conducted in KwaZulu-Natal, South Africa, used geospatial techniques to assess the relationship between ART use and HIV incidence in an observational cohort of more than 16,000 study participants living in many different communities.[33] After adjustment for sexual behaviour and prevalent HIV cases, each percentage point increase in ART coverage of people with HIV infection lowered the HIV infection risk in a community by 1.7%.

Most significantly, the multi-continental HPTN 052 trial enrolled 1,763 HIV-serodiscordant couples in which the partner with HIV was ART naïve with a CD4 count of 350 to 550 cells/μL at enrolment to compare the effect of immediate ART versus delayed therapy (not started until CD4 count < 250 cells/μL) on HIV transmission to the partner with HIV infection.[34] At study entry, 97% of the participants were in heterosexual monogamous relationships. All study participants were counselled on behavioural modification and condom use. Twenty-eight linked HIV transmission events were identified during the study period, but only one event occurred in the early therapy arm. This 96% reduction in transmission associated with early ART was statistically significant (HR 0.04; 95% CI, 0.01–0.27; p < 0.001). These results show that early ART is more effective at preventing transmission of HIV than all other behavioural and biomedical prevention interventions studied. This study, as well as other observational studies and modelling analyses showing a decreased rate of HIV transmission among serodiscordant heterosexual couples following the introduction of ART, demonstrate that suppression of viraemia in ART-adherent patients with no concomitant sexually transmitted infections (STIs) substantially reduces the risk of transmission of HIV. HPTN 052 was conducted in heterosexual couples and not in populations at risk of transmission via homosexual exposure or needle sharing. In addition, in this clinical trial, adherence to ART was well supported and near complete. However, the prevention benefits of effective ART observed in HPTN 052 can reasonably be presumed to apply broadly. Therefore, the Panel recommends that ART be offered to patients who are at risk of transmitting HIV to sexual partners (the strength of this recommendation varies according to mode of sexual transmission: AI for heterosexual transmission and AIII for male-to-male transmission and other modes of sexual transmission). Clinicians should discuss with patients the potential individual and public health benefits of therapy and the need for adherence to the prescribed regimen and counsel patients that ART is not a substitute for condom use and behavioural modification and that ART does not protect against other STIs (see Preventing Secondary Transmission of HIV).

Which regimen to use in the individual with HIV infection

When selecting a regimen for an individual patient, a number of patient- and regimen-specific characteristics should be considered, with the goal of providing a potent, safe, tolerable and easy to adhere to regimen for the patient in order to achieve sustained virological control. Some of the factors can be grouped into the following categories:

Initial characteristics of the patient

  • Pre-treatment HIV RNA level (viral load) – there are some regimens which are not recommended if RNA is > 100,000 copies/mL
  • Pre-treatment CD4 cell count
  • HIV genotypic drug resistance testing results will determine if any specific drugs should be avoided in the regimen
  • HLA-B*5701 status – HLA B*5701 positive patients should not receive abacavir-containing regimens
  • Patient preferences
  • Patient’s anticipated adherence – patients with potential adherence difficulties should be commenced on a ritonavir-boosted protease inhibitor (PI/r)-based regimen.

Specific comorbidities or other conditions

  • Cardiovascular disease, hyperlipidaemia, renal disease, osteoporosis, psychiatric illness, neurological disease, drug abuse or dependency requiring narcotic replacement therapy
  • Pregnancy or pregnancy potential
  •  Co-infections: hepatitis C virus (HCV), hepatitis B virus (HBV), tuberculosis (TB). 

Regimen-specific considerations

  • Regimen’s genetic barrier to resistance
  • Potential adverse drug effects
  • Known or potential drug interactions with other medications
  • Convenience (e.g., pill burden, dosing frequency, availability of fixed-dose combination products, food requirements)
  • Choice of a regimen that is known to be potent i.e. one which includes at least three drugs from at least two classes, generally two drugs (backbone drugs) from the nucleoside/nucleotide reverse transcriptase inhibitors (NRTI/NtRTI) class (backbone) and a third (anchor drug) from either the integrase strand transfer inhibitor (INSTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) or PI/r class
  • Choice of a regimen that is currently recommended by the Australian Antiretroviral Guidelines Panel: alternatives to currently recommended therapy should generally only be used in the context of a specific clinical indication. 
ŸPanel's recommendations

An antiretroviral regimen for a treatment-naive patient generally consists of two nucleoside reverse transcriptase inhibitors in combination with a third active antiretroviral drug from one of three drug classes: an integrase strand transfer inhibitor, a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor with a pharmacokinetic enhancer (cobicistat or ritonavir).

The Panel classifies the following regimens as recommended regimens for antiretroviral-naive patients: Integrase strand transfer inhibitor-based regimens

  • Dolutegravir/abacavir/lamivudine—only for patients who are HLA-B*5701 negative (AI)
  • Dolutegravir plus tenofovir disoproxil fumarate (tenofovir)/emtricitabine (AI)
  • Elvitegravir/cobicistat/tenofovir/emtricitabine—only for patients with pre-antiretroviral therapy creatinine clearance > 70 mL/min (AI)
  • Raltegravir plus tenofovir/emtricitabine (AI)

Protease inhibitor-based regimen

  • Darunavir/ritonavir plus tenofovir/emtricitabine (AI)

On the basis of individual patient characteristics and needs, an Alternative regimen or; less frequently, an other regimen; may in some instances be the optimal regimen for a patient.[35]

Given the large number of excellent options for initial therapy, selection of a regimen for a particular patient should be guided by factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, comorbid conditions, and cost. Table 1 provides guidance on choosing an antiretroviral regimen based on selected clinical case scenarios.[36]

Rating of Recommendations: A: Strong; B: Moderate; C: Optional
Rating of Evidence: I: Data from randomised controlled trials; II: Data from well-designed nonrandomised trials or observational cohort studies with long-term clinical outcomes; III: Expert opinion

Note: Lamivudine may substitute for emtricitabine or vice versa in above regimens

The INSTI-based regimens were selected because of their high virologic efficacy, excellent safety and tolerability profiles, and (with RAL and dolutegravir [DTG]) low number of drug-drug interactions (see the INSTI section of the guidelines for discussion regarding the special characteristics and clinical trial results for each of the three recommended INSTIs). For patients who are at high risk for intermittent therapy because of poor adherence or have transmitted NRTI drug resistance, a PI/r-based treatment is preferred given the PIs high genetic barrier to resistance. In some situations, an NNRTI-based regimen may be a better choice for a particular patient.

Table 1 provides guidance on regimen selection based on various patient- and regimen-specific characteristics. 

Table 1. Antiretroviral regimen considerations as initial therapy based on specific clinical scenarios[37]:

Patient or regimen characteristics Clinical scenario Consideration(s) Rationale/comments

Pre-ART characteristics

 

CD4 count < 200 cells/μL Do not use the following regimens:
• RPV-based regimens
• DRV/r plus RAL
Higher rate of virological failure observed in those with low pre-treatment CD4 cell count
HIV RNA >100,000 copies/mL

Do not use the following regimens:
• RPV-based regimens
• ABC/3TC with EFV or ATV/r
• DRV/r plus RAL


Higher rates of virological failure observed in those with high pre- treatment HIV RNA
HLA-B*5701 positive   Do not use ABC-containing regimen. Do not use ABC-containing regimen ABC hypersensitivity, a potentially fatal reaction, is highly associated with positivity for the HLA-B*5701 allele
Must treat before HIV drug resistance results available Avoid NNRTI-based regimen

Transmitted mutations conferring NNRTI resistance are more likely than mutations associated with PI or INSTI resistance

Some experts avoid using INSTI-containing regimens in this setting because of concern regarding their ability to fully suppress viral replication if transmitted NRTI mutations are present 

ART-specific characteristics
One pill once daily regimen desired
ART options include:
• DTG/ABC/3TC
• EFV/TDF/FTC
• EVG/c/TDF/FTC
• RPV/TDF/FTC (if HIV RNA <100,000 copies/mL and CD4 count >200/
μL)

Available as fixed-dose combination tablets
Food effects 

Regimens that should be taken with food:
• ATV/r or ATV/c-based regimens
• DRV/r or DRV/c-based regimens
• EVG/c/TDF/FTC
• RPV/TDF/FTC

Regimens that should be taken on an empty stomach:
• EFV-based regimens

Food improves absorption of the listed regimens

Taking EFV-based regimens with food increases EFV absorption and may increase CNS side effect

Presence of other conditions Chronic kidney disease (defined as eGFR < 60 mL/min)

Consider avoiding TDF

If eGFR is < 70 mL/min, do not use:
• EVG/c/TDF/FTC, or
• ATV/c with TDF, or
• DRV/c with TDF

Options for CKD patients
Use ABC/3TC if HLA-B*5701 Negative:
• If HIV RNA > 100,000 copies/mL, do not use ABC/3TC with EFV or ATV/r.
• If CrCl < 50 mL/min, do not use coformulated ABC/3TC because 3TC requires dose adjustment

Other options (See text for discussion):
• DRV/r plus RAL (if HIV < 100,000/mL and CD4 count > 200/
μL), or
• LPV/r plus 3TC, or
• Modify TDF dose

TDF has been associated with renal tubulopathy

See Appendix B, Table 7 (in Guidelines)[38] for recommendations on ARV dose modification

Osteoporosis

Consider avoiding TDF.
ABC/3TC if HLA-B*5701 negative

If HIV RNA > 100,000 copies/mL, do not
use ABC/3TC plus (EFV or ATV/r)

TDF is associated with greater decrease in bone mineral density along with renal tubulopathy, urine phosphate wasting, and osteomalacia
Psychiatric illness Consider avoiding EFV-based regimens EFV can exacerbate psychiatric symptoms and may be associated with suicidality
HIV-associated dementia (HAD)

Avoid EFV-based regimens if possible

Favour DRV-based or DTG-based regimen

EFV neuropsychiatric effects may confound assessment of the effect of ART on improvement of symptoms associated with HAD


Theoretical CNS penetration advantage

Narcotic replacement therapy required

If patient receiving methadone, consider avoiding EFV-based regimen.

If EFV is used, an increase in methadone dose may be necessary

 EFV reduces methadone concentrations and may lead to withdrawal symptoms
 High cardiac risk Consider avoiding ABC- and LPV/r - based regimens  Increased cardiovascular risk in some studies (see ABC discussion in the guidelines
Hyperlipidaemia

The following ARV drug classes or drugs have been associated with deleterious effects on lipids:

• PI/r
• ABC
• EFV
• EVG/c

TDF has been associated with beneficial lipid effects, thus it may be preferable to ABC
Pregnancy Refer to the Perinatal Antiretroviral Treatment Guidelines.

Presence of co- Infections

 

HBV infection

Use TDF/FTC (or TDF plus 3TC) whenever possible

If TDF is contraindicated:

  • For treatment of HBV, use FTC or 3TC with entecavir or another drug active against HBV

TDF, FTC, and 3TC are active against both HIV and HBV. 3TC- or FTC-associated HBV mutations can emerge rapidly when these drugs are used without another HBV-active agent
HCV treatment required Refer to recommendations in the HIV/HCV co-infection section of the guidelines
Tuberculosis infection

If rifampin is used:

  • EFV-based regimens have the least drug- drug interactions
  • If RAL is used, increase RAL dose to 800 mg twice daily
  • Use DTG at 50 mg twice daily dose only in patients without selected INSTI mutations (refer to product label)

If using a PI-based regimen, rifabutin should be used in place of rifampin in the tuberculosis regimen

  • Rifampin is a strong inducer of CYP3A4 and UGT1A1 enzymes, causing significant decrease in concentrations of PI, INSTI, and RPV
  • Rifampin has a less significant effect on EFV concentration than on other NNRTIs, PIs, and INSTIs
  • Rifabutin is a less potent inducer and is a good option for patients receiving non- EFV-based regimens
Refer to Tables 19a, b, d and e for dosing recommendations for rifamycins used with different ARV agents in the guidelines

3TC: lamivudine; ABC: abacavir; ATV/r: ritonavir-boosted atazanavir; ART: antiretroviral therapy; ARV: antiretroviral; c: cobicistat; CKD: chronic kidney disease; CrCl: creatinine clearance; DRV/r: ritonavir- boosted darunavir; DTG: dolutegravir; eGFR: estimated glomerular filtration rate; EFV: efavirenz; EVG/c/TDF/FTC: elvitegravir/cobicistat/tenofovir/emtricitabine; FDA: Food and Drug Administration; FTC: emtricitabine; HBV: hepatitis B virus; HCV: hepatitis C virus; INSTI: integrase strand transfer inhibitor; LPV/r: ritonavir-boosted lopinavir; NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; r/PI: ritonavir-boosted protease inhibitor; RAL: raltegravir; RPV: rilpivirine; RTV: ritonavir; TDF: tenofovir disoproxil fumarate

Antiretroviral treatment strategies

Acute or primary HIV infection

Improved recognition of the clinical syndrome suggestive of acute HIV or primary HIV infection combined with use of newer diagnostic tests enables early identification of this group of individuals and thus consideration of antiretroviral therapy.

The SPARTAC study randomised patients with primary HIV infection to 48 weeks vs 12 weeks vs standard of care (no treatment) with follow-up to measure end point of CD4 count < 350 cells/μL. The 48-week treatment arm had significantly fewer patients reaching CD4 < 350 cells/μL average follow up 42 months.[39] There are potential benefits from treating patients with primary HIV infection including clinically reducing the flu-like symptoms characteristic of primary infection which can be severe, reduced seeding of the viral reservoirs, alteration of virological set point, reduced immunological damage and rapid immunological recovery, and finally, less opportunity for the development of viral resistance mutations.[40][41] The potential disadvantages of initiating cART in primary infection include patient readiness to commence ART at the time of managing the psychological and physical effects of a new HIV diagnosis, particularly since cART requires ongoing life-long adherence. There can be a delay in obtaining a baseline resistance result before commencement of cART.

ART is recommended for all people with HIV infection and should be offered to those with acute HIV infection (BII), although definitive data are lacking as to whether this approach will result in long-term virologic, immunologic, or clinical benefits.[42] For patients with early HIV infection in whom therapy is initiated, testing for plasma HIV RNA levels, CD4 count, and toxicity monitoring should be performed as described for patients with chronic HIV infection.

Genotypic drug resistance testing should be performed before initiation of ART to guide the selection of the regimen (AII). If therapy is deferred, genotypic resistance testing should still be performed because the results will be useful in selecting a regimen with the greatest potential for achieving optimal virological response when therapy is ultimately initiated. ART can be initiated before drug resistance test results are available. Since resistance to ritonavir (RTV)-boosted PIs emerges slowly and since clinically significant transmitted resistance to PIs is uncommon, these drugs combined with NRTIs should be used in this setting (AIII).

Patients starting ART should be willing and able to commit to treatment and should understand the possible 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 because of clinical or psychosocial factors.

Treatment interruption

Treatment interruption following initiation of ART is not recommended apart from specific short-time situations. The SMART study, which examined ART interruption as a potential method of reducing ART exposure and thus ART toxicity, resulted in significantly higher rates of AIDS, severe non-AIDS events and death in the treatment interruption arm.[43][44]

Antiretroviral treatment in specific clinical scenarios

HIV and hepatitis C co-infection

HIV-hepatitis C virus (HCV) co-infection is increasingly prevalent in Australia, affecting approximately 10% of those with HIV, and with clinical consequences for both diseases. The rate of progression of liver disease from hepatitis C has long been known to be accelerated in the setting of co-infection and a recent meta-analysis demonstrated the risk of cirrhosis to be three-fold higher when compared with an HIV-negative control population.[45][46] Standard-of-care therapy for individuals with HCV mono-infection up to recently consisted of pegalated interferon plus ribavirin (IFN/RBV). In patients with HIV-HCV co-infection, sustained virological response rates of approximately 60-70% for genotype 2/3 and 25% for genotype 133,[47] (the most common genotype in Australia) have been shown. Response rates in genotype 1 have been increased with the addition of an NS3A inhibitor to IFN/RBV, (previously bocepravir or telapravir were used,[48][49] although at the cost of greater toxicities), and more recently simepravir has provided beneficial responses with lower toxicity and lower pill load.[50]

There has been a revolutionary advance in treatment of HCV infection with the advent of direct-acting antiviral (DAA) agents which in some cases can be coforumulated, but can provide oral-only therapy, (depending on HCV genotype, stage of liver disease and prior treatment, DAA therapy is given with or without ribavirin, for 12-24 weeks) with sustained virological response 12 weeks after cessation of therapy (SVR12) which is cure, in over 90-95% of patients treated. Not only do DAAs provide excellent efficacy and tolerability, the results seen in patients with HIV co-infection are the same as those seen in patients with mono HCV infection.[51]

A number of DAAs such as sofosbuvir-ledipasvir and daclatasvir, have been approved by the Therapeutic Goods Administration (TGA) in Australia, while the Pharmaceutical Benefits Scheme (PBS) reimbursement is pending and expected in the near future. It is expected that the prescribing of DAAs will be broadly permitted for all patients with chronic HCV, regardless of stage of disease.

Low-grade abnormalities of liver function tests are common in HCV and HIV infection, regardless of treatment status. A common practical problem facing the clinician following the initiation of ART in the person with HIV-HCV co-infection is worsening liver function tests. All classes of antiretroviral drugs have been associated with hepatotoxicity.[52][53] The NNRTI, nevirapine, is associated with the greatest estimated hepatotoxicity, with two-thirds of the episodes of clinical hepatitis occurring within 3 months of starting nevirapine.[54] This risk however can be significantly reduced by following the guidelines regarding CD4 cell criteria discussed above. As a general rule nevirapine should be used with caution in individuals with co-infection with cirrhosis. In some instances following commencement of ART, elevation of liver enzymes has been associated with a transient rise in HCV RNA,[55] attributed by some to immune restoration disease (IRIS). IRIS is particularly a risk where patients initiate cART at low CD4 cell levels. At present the relative contributions of hepatitis C and antiretrovirals to hepatic toxicity remain uncertain. A practical approach to this problem includes avoidance of antiretroviral agents with a known association with significant hepatotoxicity and further evaluation of hepatitis C disease (see Hepatitis C co-infection section). Mild abnormalities in liver function in the setting of HIV infection can be observed, but in cases of severe hepatotoxicity (elevation of enzymes greater than five times normal)[56] antiretroviral therapy should be withdrawn. Another potential cause of liver toxicity relates to mitochondrial damage due to NRTIs. This effect has markedly reduced in the context of waning use of stavudine and didanosine.

In the past, decisions were required by the clinician on which virus to treat first in patients with HIV-HCV co-infection. However, in the rapidly changing landscape of HIV and HCV therapy, all patients with HIV should be commenced on cART unless specific reasons preclude this procedure; all patients with HIV-HCV co-infection will be offered oral DAA anti-HCV regimens associated with > 90% HCV cure. There are specific drug-drug interaction between some DAAs or ribavirin and specific antiretrovirals, as well as between DAAs and some other therapies patients may be taking. It is recommended to consult a current drug-drug interaction website with up-to-date information prior to commencing a patient on HCV therapy e.g. the site provided by the University of Liverpool, UK: http://www.hep-druginteractions.org

HIV and hepatitis B co-infection

Morbidity and mortality related to liver disease secondary to chronic hepatitis B virus (HBV) infection in the context of HIV infection are increasing. The diagnosis of HIV-HBV co-infection has implications for the treatment of both infections. The two viruses, although classified in different families, have a number of similarities in replication pathways including a reverse transcription step (with the reverse transcriptase enzyme being virally encoded) and a number of analogous gene products. As a result, some reverse transcriptase inhibitors are active against both viruses. In addition, as is seen in HCV-HIV co-infection, progression of liver disease from chronic hepatitis B is accelerated with HIV co-infection.[57] Unlike HCV, which can potentially be cured, HBV treatment at this stage needs to be continued indefinitely.

Treatment decisions in individuals with HIV-HBV co-infection are predicated upon whether neither or both viruses require treatment, or if only one of the viruses require treatment. In addition to the usual HIV parameters used in guiding therapy, severity of liver disease, likelihood of response and risk of adverse events should be considered. Detailed treatment algorithms may be found in a review of the topic.[58] To date the US Food and Drug Administration (FDA) have approved seven agents for the treatment of chronic hepatitis B,[59][60][61][62][63] including interferon alpha-2b, pegylated interferon alpha-2a, lamivudine, tenofovir, adefovir, entecavir, telbivudine and emtricitabine. In Australia, pegylated interferon alpha-2a, lamivudine, tenofovir, adefovir, telbivudine and entecavir are available under the Australian Government’s Highly Specialised Drugs Program as Section 100 (S100) items for the treatment of hepatitis B.

Case Study 1. A man with a rash attends his local clinic 
A 44-year-old man from Indonesia, previously known to have HIV infection, presented to his local medical officer with an unusual rash. He had no follow-up for HIV since diagnosis and was antiretroviral naïve. His CD4 cell count was 50 cells/μL and plasma HIV RNA was over 100,000 copies/mL. Investigation revealed elevated hepatic transaminase levels of twice normal. Hepatitis B surface antigen (HBsAg), hepatitis B envelope antibody (HBeAg) and anti-hepatitis B core antibody (anti-HBcAb) and hepatitis A IgG were detected. Delta antigen and antibody were not detected; HCV antibody was not detected and HCV polymerase chain reaction (PCR) was negative.

His doctor started prednisolone 50 mg daily for the rash, with rapid dose reduction, and 2 weeks later started combivir, efavirenz and cotrimoxazole. Fourteen days later, the man developed pain in the right upper quadrant and jaundice. Examination revealed tender hepatomegaly, but no splenomegaly or signs of chronic liver disease. He had oropharyngeal candidiasis. Liver function tests revealed an alanine aminotransferase of 3900U/L, gamma-GT of 390 U/L, alkaline phosphatase of 97 U/L and bilirubin of 297μmol/L. His albumin was 28 g/L and platelet count was 57 x 109/L. Coagulation was abnormal. A diagnosis of acute exacerbation of chronic hepatitis B was made. The patient’s hepatitis B virus (HBV) DNA was 266 IU/L His course was complicated by haematemesis and melaena from severe ulcerative oesophagitis, development of hepatic encephalopathy, persistent coagulopathy, and acute renal failure. He died 6 weeks after commencing antiretroviral therapy.

This man did not have an assessment of the severity of the chronic HBV before starting antiretroviral therapy (which included only a single agent with activity against hepatitis B: lamivudine). In addition, empirical use of prednisolone in this situation should be undertaken with great caution. The course in this man was complicated by the prednisolone withdrawal, which is known to cause a hepatitis flare in patients with HBV infection.

Consideration of antiretroviral therapy in patients with HIV and HBV co-infection should include:

  • Assessment of other potential causes of liver disease including non-infectious causes, serology for HCV, hepatitis A virus and hepatitis D virus, and HCV PCR, and assessment of level of HBV replication by quantitative HBV DNA PCR assay. Additionally consider other tropical infections, particularly if this patient is not from an urban Indonesian area.
  • Liver imaging and coagulation parameters and consideration of liver biopsy to determine degree of necroinflammatory and fibrotic changes present.
  • Counselling regarding alcohol intake and other hepatotoxic agents.
  • Advice regarding vaccination for hepatitis A if not immune, safer sexual behaviour and travel advice.
  • Choice of antiretroviral regimen directed against both HIV and hepatitis B, with avoidance of ritonavir and nevirapine;
  • Advice about avoidance of treatment interruption: removal of anti-HBV agents may cause a severe flare in liver disease.
  • Regular monitoring of markers of liver disease in response to anti-HBV and antiretroviral therapy.

In situations where therapy for hepatitis B alone is indicated, consideration may be given to treatment with pegylated interferon alpha-2a, which is more effective than standard interferon.[64] Adefovir is generally avoided due to concerns regarding potential development of HIV resistance (this agent is closely related to tenofovir), nephrotoxicity and data showing its inferiority to tenofovir.[65] If lamivudine, emtricitabine or tenofovir is chosen it should only be administered in the context of a fully suppressive cART regimen that includes both tenofovir and either lamivudine or emtricitabine. Use of lamivudine alone is well documented to be associated with the rapid development of resistance mutations to HIV while use of lamivudine in a cART regimen without another agent active against hepatitis B e.g. lamivudine/emtricitabine (3TC/FTC) will lead to HBV resistance mutations in 94% of individuals by 4 years. While entecavir was initially believed not to have activity against HIV, a recent report showed that its use was associated with a 1 log drop in HIV viral load and selection of the M184V resistance mutation of HIV, thus conferring lamivudine resistance. In light of these data, entecavir should only be used in the context of a fully suppressive cART regimen.[66] Telbivudine in HIV-HBV co-infection is safe and efficacious although there is cross resistance with M204 lamivudine hepatitis B resistance mutation.[67]

In situations where therapy for both viruses or HIV alone is indicated, a fully suppressive cART regimen should be commenced, with the NRTI backbone including either lamivudine or emtricitabine and tenofovir.

All patients commencing therapy should be counselled regarding the risks of cessation of HBV active agents as a severe flare of liver disease may result. Liver function should be monitored carefully as immune reconstitution flares may occur. Development of abnormal liver function tests may indicate impending HBeAg seroconversion,[68] which is readily confirmed by checking HBeAg and eAb.

HIV infection in women

Women tend to be under-represented in clinical trials examining HIV therapies. The indications for initiation of ART and the goals of treatment are the same for women with HIV infection as for other adults and adolescents with HIV (AI).[69][70] Nevertheless, some large scale studies in women such as GRACE and WAVES that examined ART initiation, showed similar efficacy and safety as in men.[71][72]

It is generally recommended that NVP not be prescribed to antiretroviral- naïve women who have CD4 counts > 250 cells/μL unless there is no other alternative and the benefit from NVP outweighs the risk of hepatotoxicity (AI).

There is a female predominance in the increased incidence of symptomatic and even fatal lactic acidosis associated with prolonged exposure to NRTIs, particularly with stavudine (d4T), didanosine (ddI) and zidovudine (ZDV).[73]

Women with HIV infection are more likely to experience increases in central fat with ART and are less likely to have triglyceride elevations on treatment.[74] Women have an increased risk of osteopenia/ and osteoporosis, particularly after menopause, and this risk is exacerbated by HIV and ART.[75]

For women taking oral contraceptives, consideration should be given for potential drug-drug interactions with ART, and choice of therapy or alternative forms of contraception may need to be considered.

For women considering pregnancy and for women of childbearing age not taking adequate contraception, efavirenz should be avoided. Efavirenz has a risk during the first 4-6 weeks of pregnancy of neural tube defects found with this drug in animal studies. Women taking an efavirenz-containing regimen and realised to be pregnant, who have virological suppression, may continue with this therapy if they have passed the initial 6 weeks.[76]

The goals of management of pregnancy include maternal virological suppression that will be beneficial to the mother and reduce the risk of HIV perinatal transmission.

When designing a regimen for a pregnant woman, clinicians should consult the most current Health and Human Services (HHS) Perinatal Guidelines (AIII).

Women of childbearing potential

All women of childbearing potential should be offered pre-conception counselling and care as a component of routine primary medical care.

Hormonal contraception

See HIV and Pregnancy chapter

Safe and effective reproductive health and family planning services to reduce unintended pregnancy and perinatal transmission of HIV are an essential component of care for women with HIV of childbearing age. Counselling about reproductive issues should be provided on an ongoing basis.

Providers should be aware of potential interactions between antiretroviral drugs and hormonal contraceptives that could lower contraceptive efficacy. Several PIs and NNRTIs have drug interactions with combined oral contraceptives. Interactions include either a decrease or an increase in blood levels of ethinyl estradiol, norethindrone or norgestimate which potentially decreases contraceptive efficacy or increases estrogen- or progestin-related adverse effects (e.g., thromboembolism). Small studies of women with HIV infection receiving injectable depot-medroxyprogesterone acetate (DMPA) while on ART showed no significant interactions between DMPA and EFV, NVP, nelfinavir (NFV), or NRTI drugs.[77] Contraceptive failure of the etonogestrel implant in two patients on EFV-based therapy has been reported and a study has shown EFV may decrease plasma progestin concentrations of combined oral contraceptives containing ethinyl estradiol and norgestimate.[78] Several RTV-boosted PIs decrease oral contraceptive estradiol levels.[79] A small study from Malawi showed that NVP use did not significantly affect estradiol or progestin levels in women with HIV.[80] Overall, data are relatively limited and the clinical implications of these findings are unclear. The magnitudes of change in drug levels that may reduce contraceptive efficacy or increase adverse effects are unknown. Concerns about pharmacokinetic interactions between oral and implant hormonal contraceptives and antiretroviral agents should not prevent clinicians from prescribing hormonal contraceptives for women on ART if that is their preferred contraceptive method. However, when women wish to use hormonal contraceptives and drug interactions with antiretroviral agents are known, additional or alternative contraceptive methods may be recommended. (Consistent use of male or female condoms to prevent transmission of HIV and protect against other sexually transmitted infections [STIs] is recommended for all women with HIV infection and their partners, regardless of contraceptive use).

Intrauterine devices (IUDs) appear to be a safe and effective contraceptive option for women with HIV infection.[81] Although studies have focused primarily on non-hormone-containing IUDs (e.g., copper IUD), several small studies have also found levonorgestrel-releasing IUDs to be safe and not associated with increased genital tract shedding of HIV.[82]

Approach to pregnancy in women with HIV infection

See HIV and Pregnancy chapter

HIV infection in children

Most HIV-specialist clinicians in Australia will rarely, if ever, face the multiple challenges of managing an infant or young child with HIV infection. Ideally management should be directed by a clinician with experience in this area. The recognition of a number of differences in HIV infection between adults and children has led to some specific recommendations in paediatric practice. The US guidelines for the use of antiretroviral agents in paediatric HIV infection provide a comprehensive summary of management issues.[83] Specific considerations in the management of the child with HIV infection include:

  • Perinatal transmission (i.e. known time of infection and immature immune system)
  • In utero, intrapartum and postpartum exposure to zidovudine and other antiretroviral drugs
  • Use of virological assays for diagnosis in infants aged under 18 months
  • Differences in monitoring infection and threshold for therapy due to differences in CD4 cell counts, virological responses and clinical progression
  • Changes in drug metabolism and clearance with age
  • Issues of adherence to therapy, especially in adolescents. 

Clinical progression in children

HIV infection in children is markedly more aggressive. One quarter of children who acquire HIV infection by vertical transmission progress to AIDS within the first year (rapid progressors), and the remainder progress to AIDS over 5 years (slow progressors). Typical early signs include candidiasis, lymphadenopathy, hepatomegaly, splenomegaly and growth impairment. Common opportunistic infections include Pneumocystis jirovecii pneumonia, fungal infections, bacterial infections (particularly with encapsulated bacteria), mycobacterial infection and recurrent herpes zoster. The progression risk at given CD4 cell count levels in children over 5 years of age equate to that of adults. Due to the risk of rapid clinical progression, ART is recommended for all infants with HIV infection aged less than 12 months.[84]

CD4 cell count in children

Children naturally have considerably higher and more variable CD4 cell counts than adults. As a result, the CD4 cell thresholds used to gauge the risk of opportunistic infection and progression have been adapted to the immunological development of infants and children with HIV infection. In addition, in children under the age of 6 years, CD4 cell percentage is more reliable than CD4 cell count.

Plasma HIV RNA in children

In infants who acquire HIV perinatally, the mean plasma HIV RNA level in the first year of life is 185,000 copies/mL, while rapid progression and death has been predicted by plasma HIV RNA > 299,000 copies/mL. There may be overlap in levels between those who progress rapidly versus slowly. Regardless of plasma HIV RNA level, a CD4 cell count of less than 15% is highly predictive of disease progression and death.

Antiretroviral drug treatment recommendations in children

Specific recommendations regarding therapy initiation in children are summarised in Table 2. Regardless of the manufacturers recommendations, the current US guidelines state that all antiretroviral agents approved for use in adults may be considered in children.

Table 2. Indications for initiation of antiretroviral therapy in children with HIV infection[85]

 Age Criteria  Recommendation 
 <12 months Regardless of clinical symptoms, immune status, or viral load Urgent treatment (AI for <12 weeks of age; AII for≥ 12 weeks)
1 to <6 years      CDC Stage 3-defining opportunistic illnessesb Urgent treatment (AI*)
CDC Stage 3 immunodeficiency:d CD4 <500 cells/mm3 Urgent treatment (AI*)
Moderate HIV-related symptomsb Treat (AII)
HIV RNA > 100,000 copies/mLc Treat (AII)
CD4 cell countd 500-999 cells/mm3 Treat (AII)
Asymtomatic or mild symptoms and CD4 cell countd  1000 cells/mm3 Consider treatment (BIII)
≥ 6 years      CDC Stage 3-defining opportunistic illnessesb Urgent treatment (AI*)
CDC Stage 3 immunodeficiency:d CD4 <200 cells/mm3 Urgent treatment (AI*)
Moderate HIV-related symptomsb
Treat (AII)
HIV RNA > 100,000 copies/mLc
Treat (AII)
CD4 cell count 200-499 cells/mm3 Treat (AI* for CD4 cell count <350 cells/mm3 and AII* for CD4 cell count 350-499 cells/mm3)
Asymptomatic or mild symptomsb and CD4 cell count ≥ 500 cells/mm3 Consider treatment (BIII)
Rating of recommendations: a=Strong; B=moderate; C=Optional
 
Rating of Evidence: I= data from randomised controlled trials in children; I*=data from randomised trials in adults with accompanying data in chldern from nonrandomised trials or observational cohort studies with long-term clincial outcomes; II*=data from well-designed non randomised trials or observational cohort studies in adults with long-term clinical outcomes with accompanying data in children from smaller non-randomised trials or cohort studies with clinical outcomes data; III=Expert opinion
  1. Children in whom cART is deferred need close follow-up. Factors to consider in deciding when to initiate therapy in children whom treatment was deferred include: CD4 cell count or percentage values approaching the age-related threshold for treatment; Development of clinical symptoms; and The ability of caregiver and child to adhere to the prescribed regimen.
  2. To avoid overinterpretation of temporary blips in viral load (which can accour during intercurrent illnesses, for exmaple), plasma HIV RNA level > 100, 000 copies/mL should be confirmed by a second level before initiating cART.
  3. Laboratory data should be confirmed with a second test to meet the treatment criteria before initiation of cART.

HIV-associated neurocognitive disorders

In the cART era, HIV-associated neurocognitive disorders (HAND) have not diminished in prevalence which ranges from 25-40% of individuals with HIV. However, the more severe forms of HIV-associated dementia (HAD) are seen less frequently, in contrast to the more frequent milder forms of mild neurocognitive disorder (MND) and asymptomatic neurocognitive impairment (ANI). Some key points to consider:

  • Currently there are no optimally available screening tools in the clinic to detect HAND
  • Dementia may be seen in individuals on cART as well as those who are treatment naïve or have ceased cART
  • Late commencement of cART and failure to recognise dementia are likely to be significant factors
  • Thorough evaluation (neuroimaging, neuropsychological testing and cerebrospinal fluid (CSF) examination) is indicated to exclude other causes and confirm the diagnosis
  • CART improves the cognitive impairment due to HIV- associated dementia[86][87]
  • Consideration should be given to the use of antiretroviral agents, which penetrate the central nervous system[88]
  • Rarely, differential patterns of resistance mutations may be seen in plasma versus CSF[89]
  • Individuals with HIV-associated dementia often have a very slow response to therapy over months rather than weeks
  • During this time it may be necessary to institute directly observed therapy in a supported environment
  • Cognitive impairment is frequently associated with poor medication adherence.

CasStud2. Patient with short-term memory loss

A 56-year-old man presents with short-term memory loss and a generalised epileptic fit. HIV is diagnosed and no opportunistic infection or other contributing factor is identified on brain-imaging studies. He lives alone, is dishevelled in appearance, and has lost weight recently.

Management of this man includes:

  • Baseline screening for dementia, and assessment of the severity of dementia, using formal neuropsychological testing
  • Assessment of cerebrospinal fluid HIV RNA, MRI and surrogate markers (CD4 cell count, plasma HIV RNA)
  • Specialist neurological review
  • Commencing ART, (possibly with CNS penetrating ART) if diagnosed with HIV-associated neurocognitive disorder (HAND)
  • Consideration of directly observed therapy with agents which may be dosed once-daily
  • Monitoring of clinical, radiological and cerebrospinal fluid response to therapy, including HIV RNA in both plasma and cerebrospinal fluid and consideration of compartmentalisation of resistant virus in the central nervous system if response is suboptimal.

HIV and drugs of dependence

The prevalence of HIV infection in people who inject drugs (PWID) in Australia, assuming no other risk factors for acquisition, is approximately 2%.[90] The prevalence of HIV in Australian male homosexual PWID is much higher however, at 32%.[91] Despite the relatively low numbers involved, the management of HIV infection in this group presents unique challenges. Poorer outcomes in PWID with HIV infection are related to a variety of factors including increased rates of non-HIV related deaths, hepatitis C, delayed access to effective treatment, lower adherence to treatment regimens, continuation of illicit drug use, depression and negative life events.[92]

Clinical implications

CD4 cell count and plasma HIV RNA provide prognostic information[93] and progression does not appear to be influenced by means of acquisition of HIV infection.[94] A range of infections occurs more commonly in PWID with HIV infection,[95] including: 

  • bacterial infections (e.g. septicaemia, infectious endocarditis and pneumonia)
  • sexually transmissible infections (especially in sex workers)
  • tuberculosis
  • co-infection with HBV or HCV In addition, regular or intermittent use of illicit drugs may complicate assessment of psychiatric symptoms or confusional states.

Treatment implications

Social disadvantage, psychiatric comorbidity, previous incarceration, and a history of sex work are common associations of HIV infection in PWID. These circumstances impact on interactions with health-care professionals, health-care delivery and adherence to antiretroviral therapy. It is important to approach these people in a non-judgmental manner, in order to develop a relationship based on trust and mutual respect. Studies have demonstrated decreased uptake of ART and higher use of non-cART regimens in PWID. Initiation of cART has been associated with decreased use of injecting drugs and concurrent methadone.[96]

Drug interactions in methadone- and buprenorphine-treated individuals receiving cART are an important consideration. (Tables 3 and 4) As methadone is metabolised by the cytochrome p-450 system there are significant interactions with NNRTIs and some PIs, in particular. Concomitant efavirenz or nevirapine and methadone administration has precipitated opioid withdrawal symptoms. Stabilisation necessitates a substantial increase in methadone dosage.[97] There are significantly less drug interactions with buprenorphine; however, attention to potential drug interactions and education of the individual regarding the possible outcomes are required.

Table 3. Antiretroviral-methadone interactions
Antiretroviral Interaction Recommendations
Non-nucleoside reverse transcriptase inhibitors  

Efavirenz

 

Efavirenz decreases methadone Cmax and AUC by mean 60% in PK study of patients on methadone maintenance

Symptoms of opioid withdrawal have been reported from 4 days to 4 weeks after the introduction of efavirenz

 

Monitor for symptoms of opioid withdrawal and increase methadone dose as required

PK study: increase methadone dose in increments of 5-10 mg until symptoms resolved (22 - 55% increase in methadone dose reported)

Nevirapine  

Nevirapine decreases methadone AUC by 50-70% in PK study of patients on stable methadone dose.

30% of 45 patients in a prospective study of PWID on methadone maintenance required increase in methadone dose

 

As for efavirenz (above). In PK study 16% mean increase in methadone dose required.

Other case reports have required increase of 33% and 100% in methadone dose

Etravirine

No significant effects

No dosage adjustment necessary
Rilpivirine R-methadone AUC decreased by 16% No dosage adjustment necessary but monitor for opioid withdrawal
Protease inhibitors  
Atazanavir

Small PK study showed no effect and no symptoms of opioid withdrawal observed
Decreased atazanavir levels have been observed

Can be used safely in combination without dose adjustment
Monitor atazanavir levels

Darunavir/ritonavir R-methadone decreased by 16%

No dosage adjustment necessary but monitor for opioid withdrawal

Lopinavir/ritonavir

Lopinavir/ritonavir decreases methadone AUC and Cmax
~50% in PK study of healthy volunteers on methadone

Monitor for symptoms of opioid withdrawal and increase dose if necessary
Fosamprenavir/ritonavir PK study showed decrease AUC and Cmax by 20% for active methadone and 40% for inactive methadone. No change in fosamprenavir or opioid withdrawal

Combination appears safe without modification

Indinavir

No significant effect of indinavir on methadone AUC when compared with historical controls in PK study
No significant effect of methadone on indinavir AUC, but increase indinavir Cmin 50-100% and decrease indinavir Cmax 16-36% (All historical controls)

Combination appears safe
Ritonavir/saquinavir PK studies have demonstrated a clinically insignificant decrease in unbound methadone levels, and there was no evidence of opiate withdrawal There has been one case report of opioid withdrawal requiring an increase in methadone dose Monitor for symptoms of opioid withdrawal and increase dose if necessary
Tipranavir/ritonavir

PK study showed large (50%) decrease in methadone levels

Dosage of methadone may need to be increase

Amprenavir Preliminary data from PK study: decreases AUC methadone 12-24% Combination appears safe based on preliminary data
Nucleoside reverse transcriptase inhibitors  
Abacavir

No significant change in Cmax, half-life or renal clearance of methadone despite slight increase in methadone clearance by abacavir. Slight delay in rate but not extent of abacavir absorption by methadone

Combination appears safe
Didanosine,stavudine

PK study demonstrated d4T AUC decreased by 23% and ddI AUC decreased by 57%.
Effect predominantly related to reduced bioavailability

No data to guide dose adjustments. Monitor for virological failure
Zidovudine Two  PK  studies  have  demonstrated  zidovudine  AUC increase 29-43% Monitor for zidovudine related toxicities
Tenofovir PK study showed no change in kinetics of methadone

Combination appears safe

Integrase inhibitors  
Dolutegravir

No significant effect

No dosage adjustment necessary
Elvitegravir / cobicistat / tenofovir / emtricitabine

No significant effect

No dosage adjustment necessary
Raltegravir No significant effect No dosage adjustment necessary
Other  
Maraviroc No data; potentially safe in combination Monitor clinically

AUC: area under the curve; PK: pharmacokinetics; Cmax: maximum concentration achieved; Cmin: trough concentration; PWID: people who inject drugs


Source
Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Department of Health and Human Services. With Australian commentary.[98] Available at: http://arv.ashm.org.au/arv-guidelines/drug-interactions

McCance-Katz EF, Sullivan LE, Nallani S. Am J Addict 2010;19:4-16.74

 

Table 4. Interactions between buprenorphine and antiretroviral agents

Mild-moderate enzyme inhibitors Potent enzyme inhibitors Enzyme inducers

Atazanavir
Darunavir
Efavirenz
Elvitegravir
Fosamprenavir Indinavir Nelfinavir Saquinavir

 

 

Lopinavir/ritonavir Ritonavir

Efavirenz

Nevirapine

Tipranavir
Rilpivirine

Potential increase in opioid concentration  

Potential increase in opioid concentration

 

Potential decrease in opioid concentration

Atazanavir: reports of opioid excess when used in combination due to increased BUP levels, no significant change in ATV levels. If on boosted ATZ (with ritonavir) may initiate BUP slowly and at reduced dose; if on BUP consider dose reduction when initiating ATV
Do not co-administer BUP with unboosted ATZ

Darunavir: norbuprenorphine AUC increased by 46% and Cmin increased by 71%. No dosage adjustment necessary but clinical monitoring is recommended

Efavirenz: BUP AUC decreased by 50% and norbuprenorphine AUC by 71%. Monitor for opioid withdrawal symptoms

Elvitegravir: BUP AUC increased by 35% and norbuprenorphine by 42%. No dosage adjustment necessary but clinical monitoring recommended
Raltegravir – no significant interactions
Dolutegravir- no significant interactions

Lopinavir/ritonavir: addition not associated with significant change in AUC for BUP and clinical status unchanged

Efavirenz: addition associated with 50% decrease in AUC of BUP, but no clinical evidence of opioid withdrawal. No effect on efavirenz
No dose adjustment necessary for nevirapine or rilpivirine but monitor for opioid withdrawal


Source

Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Department of Health and Human Services. With Australian commentary.[99] Available at
http://arv.ashm.org.au/arv-guidelines/drug-interactions 
McCance-Katz EF, Sullivan LE, Nallani S. Am J Addict 2010;19:4-16.[100]
University of Liverpool, drug interactions tables available at http://www.hiv-druginteractions.org/

BUP: buprenorphine; ATV: atazanavir; AUC: area under the curve.

Harm minimisation strategies

Minimisation of risk to the individual and the community is the basis of the public health approach to HIV infection. Rates of transmission of HIV infection among PWID can be reduced through needle-exchange programs, access to drug-dependence treatment options such as opioid substitution therapy and education regarding sexual transmission.

Thus, optimal management of PWID with HIV infection includes a combination of specialist HIV care and expertise, and facilities for drug-dependence treatment.

Interactions between recreational drugs and antiretroviral therapy

The clinician at baseline and at regular intervals thereafter should seek information regarding current use of recreational drugs. It is important for patients to have an understanding of the (potentially dangerous) interactions between recreational drugs that are intermittently used and the antiretroviral drugs that are taken regularly. Table 5 summarises demonstrated and theoretical interactions between recreational drugs and antiretroviral agents. The recent increase in use of crystal methamphetamine in men who have sex with men in Australia is worth particular mention as is the fact that methamphetamine was the most commonly reported drug last injected among HIV antibody positive respondents in the Australian NSP survey in all survey years between 2009-13).[101] Associated phenomena and complications of use of this drug are well summarised elsewhere.[102] Although formal data regarding drug interactions are not available, methamphetamine is likely to be potentiated by ritonavir in a similar manner to mythylenedioxymethamphetamine (MDMA). Patients should be advised to reduce the dose of crystal methamphetamine to one-quarter to one-half of normal. There is one report in the literature of an individual in Melbourne whose death was suspected to be due to the combination of methamphetamine use with concurrent antiretroviral therapy that included ritonavir.[103]

TableInteractions between antiretroviral andrecreational drugs

Drug Interactions Recommendations

Amphetamines

Possible increased levels with ritonavir Avoid combination with RTV if possible. If not, start with 1⁄4 – 1⁄2 of initial amount of amphetamine taken
 

Codeine

Due to different pathways of metabolism may increase or decrease morphine levels Monitor for signs of opiate toxicity or withdrawal
Gamma hydroxybutyrate (GHB) (Fantasy) Possible increased levels/prolonged effect with antiretrovirals, especially RTV

Use cautiously with inhibitors of cytochrome P-450 (PIs, efavirenz). Users should be aware of signs/symptoms of GHB toxicity
(e.g. seizures, respiratory depression)

Ketamine

Possible increased levels with antiretrovirals, especially RTV, NFV and EFV

Use cautiously with cytochrome P-450 inhibitors. Users should be aware of signs/symptoms of ketamine toxicity
(e.g. hallucinations, respiratory depression)

Lysergic acid diethylmide (LSD) Unknown  

Use cautiously with cytochrome P-450 inhibitors. Users should be aware of signs/symptoms of LSD toxicity (e.g. hallucinations, psychosis, agitation)

Methylenedioxymethamphetamine (MDMA) (Ecstasy) Possible increase levels with RTV. Two deaths have been reported Avoid combining with ritonavir if possible. If not, reduce MDMA dose by about 1⁄4 – 1⁄2 of usual amount used, and watch for signs of MDMA toxicity. Other precautions include staying well hydrated, avoiding alcohol and taking breaks from dancing
Oxycodone Due to different pathways of metabolism may increase or decrease levels of active metabolite oxymorphone, resulting in possible opiate withdrawal or toxicity Monitor for signs of opiate withdrawal or toxicity
Phencyclidine (PCP) Possible increase levels with antiretrovirals

Use cautiously with cytochrome P-450 inhibitors. Ensure patient aware of signs/symptoms of phencyclidine toxicity
(e.g. seizures, rhabdomyolysis, hypertension, hyperthermia)

Tetrahydro-cannabinol (THC), active moiety of marijuana, hashish and hash oil Drugs which inhibit CYP3A4  or 2C9 (PIs) may increase THC concentrations. Drugs which induce CYP3A4 (EFV, NVP) may decrease THC concentrations. A randomised trial of the effects of cannabinoids on the pharmacokinetics of IDV and NFV: smoked THC decrease NFV AUC by 17%, and decrease IDV Cmax 21% There have been no reports documenting adverse events secondary to the combination of THC and protease inhibitors despite the wide use of THC derivatives as antiemetics and appetite stimulants

AUC: area under the curve; EFV: efavirenz; IDV: indinavir; NFV: nelfinavir; NVP: nevirapine; RTV = ritonavir.

Source: Adapted from Antoniou T, Tseng A. Ann Pharmacother 2002;36:1598-613.[104]

 

Case Study 3.      Man on methadone therapy

 

A 43-year-old man with a history of injecting drug use and heroin dependence currently maintained on methadone maintenance therapy presents for initiation of anti-HIV therapy. His HIV infection was diagnosed 8 years previously. He has monitored his surrogate markers infrequently. In recent months he has noted increasing lethargy, weight loss and cough. He currently lives in a boarding house however he has been attacked on a number of occasions and has resolved to move out. His plasma HIV RNA is above 100,000 copies/mL and CD4 cell count 210 cells/μL (14%).
Considerations when initiating therapy include:

  • assessment for occult infection (e.g. endocarditis, pneumonia, tuberculosis)
  • status of hepatitis infections and vaccination
  • address housing issue – referral to social worker or housing agency
  • formal adherence assessment and plan to support adherence when commences therapy
  • resistance testing if possible
  • consideration of drug-drug interactions with methadone (e.g. nevirapine in the cART regimen will require an increase in methadone dose)
  • consider daily regimen that may be dispensed with opioid replacement therapy assessment of social supports, and access to harm minimisation strategies.
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