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 illnesses^b	Urgent treatment *(AI)**
	CDC Stage 3 immunodeficiency:^d CD4 <500 cells/mm³	Urgent treatment *(AI)**
	Moderate HIV-related symptoms^b	Treat (AII)
	HIV RNA > 100,000 copies/mL^c	Treat (AII)
	CD4 cell count^d 500-999 cells/mm³	Treat (AII)
	Asymtomatic or mild symptoms and CD4 cell count^d ≥ 1000 cells/mm³	Consider treatment (BIII)
≥ 6 years	CDC Stage 3-defining opportunistic illnesses^b	Urgent treatment *(AI)**
	CDC Stage 3 immunodeficiency:^d CD4 <200 cells/mm³	Urgent treatment *(AI)**
	Moderate HIV-related symptoms^b	Treat (AII)
	HIV RNA > 100,000 copies/mL^c	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 symptoms^b 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

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.
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.
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.

Case Study 2. 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]

Table 5 Interactions 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.