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.

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]

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.

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.

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]