27th June 2023

HIV/AIDS

Pathophysiology and clinical features of HIV/AIDS

Pathophysiology

Human immunodeficiency virus (HIV) is a retrovirus in the Lentivirus genus. The genome of HIV is made of RNA, which is converted into DNA by a reverse transcription enzyme and then integrates this DNA into the host DNA. There are two main types of HIV: HIV 1 and HIV 2. They are morphologically very similar, but HIV-2 is less frequently seen and has lower pathogenicity.

HIV enters cells following attachment to the CD4 receptor and a co-receptor (either CCR5 or CXCR4). HIV chiefly infects CD4+ T-lymphocytes, especially when activated (hence higher risk of transmission if there is an active infection at the site of contact) and establishes quiescent infection in memory CD4+ T cells.

HIV transmission occurs as a result of contact between body fluids and mucosal surfaces or blood, most frequently in the context of penile-vaginal or penile-anal sexual intercourse. Other forms of transmission are vertical transmission (intrauterine, intrapartum or via breast milk) and via contaminated blood products or contaminated sharps.

The progression of HIV follows a set pattern following infection in most patients, however, there is variation between individuals. The first phase in HIV infection is an asymptomatic ‘eclipse’ phase during which the virus spreads through the lymphatic system. It then replicates rapidly with an increase in viral particles and a corresponding immune response. Patients may become symptomatic around this time, but this is usually with mild ‘flu-like’ symptoms. The development of HIV-specific CD8+ T-cells results in a subsequent decrease in viral load. Following this, the disease enters a chronic phase, during which there is a gradual increase in the viral load and a gradual decline in the CD4 count. After a period of years without treatment, a patient gradually develops a CD4 count <200 cells/μL, or alternatively acquires one of a set of diseases characteristic of HIV infection, and they are then said to have entered acquired immunodeficiency syndrome or AIDS. As HIV progresses and the number of CD4+ T lymphocytes declines, the complicating conditions seen are generally less and less prevalent in the population as a whole, and hence more specific to HIV.

Symptoms of HIV infection include:

• Fevers and night sweats
• Myalgia
• Weight loss
• Rash – a range of non-specific rashes, shingles, and scarring
• Lymphadenopathy
• Diarrhoea
• Fungal infection of the nails and chronic vaginal candidiasis
• Changes to neurological function due to HIV encephalopathy or HIV-associated meningitis, toxoplasmosis or cryptococcal disease
• Oral lesions, including mouth ulcers

Seroconversion

HIV seroconversion is the period during which antibodies are developed against HIV. Since some of the common testing methods for identifying HIV rely on detecting antibodies against HIV, this has in the past been used to define the point in time at which HIV is first detectable, however more recent techniques involve nucleic acid amplification of proviral DNA with polymerase chain reaction, which can detect infection earlier in the time course of the condition. By contrast, ‘viral load’ testing relies on amplification of viral RNA. Acute retroviral syndrome describes a constellation of signs and symptoms which take place during seroconversion.

• Fever (most common)
• Malaise and fatigue
• Rash
• Weight loss
• Night sweats
• Pharyngitis
• Lymphadenopathy

Less common symptoms include neurological features, gastrointestinal features of diarrhoea, nausea/ vomiting and oral ulceration. Some patients may present with atypical features during HIV seroconversion, and testing should therefore be considered in abnormal presentations in any person at risk of HIV.

Respiratory complications in HIV/ AIDS

Pneumocystis jirovecii pneumonia

Pneumocystis jirovecii (previously Pneumocystis carinii (PCP)) is an airborne transmitted unicellular fungus characteristically infecting immunocompromised patients. In HIV, P. jirovecii infection typically indicates a CD4+ T-cell count is <200/μL, whereas it is often asymptomatic in immunocompetent individuals.

P. jirovecii presents with fever, dry cough, recurrent bacterial pneumonia, and dyspnoea, sometimes with oral candidiasis and weight loss. P. jirovecii may be insidious in HIV, with symptoms over weeks prior to presentation. Auscultation may demonstrate crackles but may be normal. Chest radiography and high-resolution CT may demonstrate bilateral pulmonary interstitial infiltrates, ground-glass opacity, and pneumatoceles (cysts). Pneumocystis is not easily cultured, necessitating microscopic staining, polymerase chain reaction (PCR) or loop-mediated isothermal amplification (LAMP) testing. Broncho-alveolar lavage and induced sputum are used, whereas spontaneously produced sputum has lower sensitivity. β-D-glucan, which is found in cell walls of Pneumocystis, and some other fungi, can screen for possible Pneumocystis infection but is non-specific.

Management for P. jirovecii usually involves co-trimoxazole for 21 days, however, there is some resistance. Co-trimoxazole is also used in prophylaxis for P. jirovecii in patients with a CD4+ T cell count <200 cells/μL. Lower CD4+ T-cells indicate a poorer prognosis. Mortality is ~10% in hospitalised patients.

Reactivation tuberculosis

HIV-associated immunosuppression accelerates tuberculosis progression, either via primary infection or reactivation of latent infection, and TB accelerates CD4+ T cell loss, thereby accelerating HIV, i.e. TB and HIV both increase the rate of progression of the other disease. Patients started on antiretroviral therapy after AIDS may develop immune reconstitution inflammatory syndrome (IRIS), which is worse with TB. Immune reconstitution causes inflammation, with recurrence of TB symptoms, abscess formation and lymphadenopathy. Neurological involvement can lead to death. Clinical presentations in pulmonary TB may include haemoptysis and features of pneumonia.

More immunocompromised patients will often have less typical features of pulmonary TB:

• Lower lobe involvement
• Tuberculous pneumonia
• Miliary TB
• Hilar/ mediastinal lymphadenopathy

TB in HIV has lower bacillary loads in sputum, meaning traditional staining is infrequently positive. Tuberculin skin testing is less frequently positive in patients with lower CD4+ T-cell counts, which requires a functional Th1 cytokine response. Broncho-alveolar lavage or bronchial biopsy may therefore be needed. Cavitation is less likely, with more isolated extrapulmonary disease. TB treatment in HIV is the same as if seronegative-rifampicin, isoniazid, pyrazinamide, and ethambutol are given for two months, followed by four months of rifampicin and isoniazid. HIV infection increases the risk of adverse events associated with anti-tuberculosis medications, including:

• Skin reactions
• Drug-induced liver injury
• Peripheral neuropathy with isoniazid (pyridoxine prophylaxis is given)
• Drug interactions with antiretroviral therapy

Rifampicin strongly induces cytochrome P450 3A4, therefore, rifabutin is recommended instead in patients taking non-nucleoside reverse transcriptase inhibitors or protease inhibitors. In treatment-naïve patients, the priority is the treatment of TB before highly active antiretroviral therapy (HAART) is initiated.

Pneumonia

Bacterial pneumonia is the most common cause of infection and admission in HIV. Consequently, patients with reduced CD4+ T-cell counts are recommended to have pneumococcal vaccines. Risk factors for bacterial pneumonia in HIV include:

• Intravenous drug use
• Smoking
• Increasing age
• Lower CD4+ T-cell count

The most common organism in community-acquired pneumonia (CAP) in HIV is Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa and Staphylococcus aureus are also common. Legionella infection is more common but remains a relatively small proportion of cases. CAP in HIV presents similarly to in seronegative individuals. Chest radiography usually features unilateral consolidation in Streptococcus or Haemophilus infection, or cavitation in Pseudomonas aeruginosa or Staphylococcus aureus. Management is similar, however, macrolides (e.g. clarithromycin) need to be given alongside a beta-lactam rather than alone because of increased resistance in Streptococcus pneumoniae.

Neurological complications in HIV/ AIDS

Cerebral toxoplasmosis

Toxoplasma gondii is a parasite spread through oocysts shed by infected cats. It is usually asymptomatic in people with a functioning immune system. Cerebral toxoplasmosis causes a multifocal necrotising encephalitis in people with HIV (usually CD4+ T-cell count is <200/μL), with subacute onset. Presenting features include:

• Subacute headache
• Focal neurological deficit
• Fever
• Confusion
• Seizures
• Ataxia

Radiology demonstrates ring-enhancing focal brain lesions. Contact is confirmed using an enzyme-linked immunosorbent assay (ELISA) which detects IgG and IgM antibodies against Toxoplasma gondii in the serum. This is sensitive but not specific, as many uninfected people have positive IgG titres for Toxoplasma gondii. Lumbar puncture (LP) can be used for PCR of Toxoplasma gondii DNA, however, this does not have a high sensitivity and patients with toxoplasma encephalitis may have mass effect, increasing the risk of brain herniation with an LP. Management of cerebral toxoplasmosis involves pyrimethamine and sulfadiazine with folinic acid. Second-line treatment and primary prophylaxis is with co-trimoxazole.

Primary CNS lymphoma

CNS lymphoma is a rare, aggressive non-Hodgkin lymphoma and is an AIDS-defining malignancy. It is confined to the CNS and is usually associated with low CD4+ T-cells (<50 cells/ μL). It is strongly associated with Epstein-Barr virus infection in the context of HIV.

Presentations include:

• Focal neurological deficit
• Seizures
• Altered mental state/ behavioural change
• Features of raised intracranial pressure

Imaging is key to identifying primary CNS lymphoma. MRI with gadolinium contrast is the imaging technique of choice, which demonstrates multifocal necrotic lesions. This contrasts with primary CNS lymphoma in patients without HIV, which typically demonstrates a single lesion. Management typically involves antiretroviral therapy in addition to methotrexate. Rituximab is given on induction. CNS lymphoma with HIV has the worst prognosis of all HIV-related lymphomas.

Cerebral abscesses in HIV

Brain abscesses in patients with HIV can be caused by tuberculomas and tuberculous abscesses. Tuberculous abscesses are larger, often solitary, and demonstrate ring enhancement. Pyogenic brain abscesses are less common than lymphoma and opportunistic infections. Patients with HIV are more likely to have multiple abscesses and infection caused by several bacteria, including:

• Listeria
• Cryptococcus
• Nocardia

Presentation includes:

• Headache
• Fevers
• Meningism
• Altered mental state
• Nausea and vomiting
• Seizures
• Papilloedema
• Focal neurological deficit

Cerebral aspergillosis has a very high mortality. Management typically involves both surgery (CT-guided stereotactic drainage) and medication. Medications for HIV patients need to cover for toxoplasmosis, frequently with pyrimethamine and sulfadiazine, or clindamycin. Oedema associated with abscesses causing significant mass effect is managed with corticosteroids.

Progressive multifocal leukoencephalopathy (PML)

PML is a CNS disease caused by JC virus. JC virus is a small ubiquitous DNA virus. PML is extremely rare in immunocompetent individuals; ~80% of cases are associated with HIV. Most patients with HIV have a CD4 count of <200 cells/μL, however, over 10% of cases have a greater CD4 count. JC virus transforms in PML to cause lysis of oligodendrocytes, causing demyelination. Presenting features include:

• Seizures
• Focal neurological deficits
• Gait disturbance
• Speech disturbance
• Ataxia
• Aphasia
• Visual changes

Imaging can aid diagnosis. CT shows hypodense lesions in the white matter, while MRI is more sensitive to white matter changes. There are often multifocal lesions. CSF is useful to exclude other diagnoses, and JC virus PCR can be conducted on CSF samples. Restoration of immunity with HAART in the treatment of PML may result in immune reconstitution inflammatory syndrome (IRIS). The newly reconstituted immune system targets oligodendritic cells, causing inflammatory demyelination. The most effective treatment for PML is immune reconstitution with antiretroviral therapy. In cases of IRIS, steroids are given alongside antiretroviral medications to control inflammation.

Cryptococcal meningitis

Cryptococcus is a genus of fungi. Cryptococcal infection is caused by either Cryptococcus neoformans or Cryptococcus gattii, with C. neoformans being found in pigeon droppings and is more widespread; it is found in tropical and subtropical areas. Cryptococcal meningitis chiefly affects patients with impaired cell-mediated immunity and, therefore, primarily affects patients with HIV- and a CD4+ T-cell count <100 cells/μL.

Presentations include:

• Head pain
• Neck stiffness
• Altered mental state
• Seizures
• Stroke
• Photophobia
• Nausea and vomiting
• Speech errors
• Focal neurological features
• Skin lesions

Imaging is not always positive in cryptococcal meningitis, however, MRI is more sensitive than CT. Common findings include:

• Leptomeningeal (e.g. pia/arachnoid mater) or dura mater thickening
• Focal parenchymal oedema
• Cryptococcoma
• Pseudocysts
• Dilation of the Virchow-Robin Space (VRS)

Diagnosis usually needs identification of Cryptococcus, involving:

• CSF sampling
  • India ink staining and microscopy
  • Culture
  • Cryptococcal antigen – detected with immunoassay, latex agglutination, or lateral flow assay
  • Beta-D-glucan – may be raised
• Serum
  • Cryptococcal antigen testing has comparable sensitivity to CSF

Management usually includes IV amphotericin V deoxycholate with oral flucytosine, followed by oral fluconazole. HAART should be postponed for around four weeks.

HIV associated neurocognitive disorder (HAND)

HAND is caused by HIV in the brain and inflammation of the brain caused by immunosuppression, and results in neuropsychiatric decline. Clinical features include:

• Loss of attention/ concentration
• Motor slowing
• Altered behaviour

These may be subtle and may require repeated neuropsychiatric testing in cases of mild neurocognitive disorder to be picked up. Risk factors for HAND include: age >50; hypertension; diabetes; hypercholesterolaemia; Hepatitis C infection; recreational drug abuse and low cognitive reserve.

The most important aspect of the treatment of HAND is antiretroviral therapy and management of comorbidities.

Ophthalmic complications of HIV/ AIDS

Cytomegalovirus (CMV) retinitis

Cytomegalovirus is a herpes virus which causes eye infection in HIV. It is considered an AIDS-defining illness when present in the context of HIV. It is ubiquitous (~80% of people are seropositive) and causes eye disease predominantly in immunosuppressed individuals. Causes of underlying immunosuppression for CMV retinitis include:

• HIV
• Haematological malignancy
• Iatrogenic immunosuppression
• Solid organ transplantation

CMV is a DNA virus which establishes latency and is reactivated when there is severe immunosuppression. CMV retinitis is usually seen with a CD4+ T-cell count <50/μL. Additionally, on restoration of immunity once antiretroviral therapy is started, uveitis may occur. Most patients with CMV retinitis are asymptomatic and are detected on screening of the retina, as the inflammation often begins on the outside of the retina. Symptoms include:

• Blurred vision (most common)
• Flashing lights
• Scotomas
• Vitreal floaters

Based on clinical course, CMV retinitis can be classified into different clinical variants:

• Indolent variant – usually affects the peripheral retina, with granular retinal opacification, white lesions, with no bleeding
• Fulminant variant – dense, yellow-white lesions with opacification and haemorrhage
• Perivascular variant

CMV retinitis is usually a clinical diagnosis made by fundoscopy. Characteristic features of the retina on fundoscopy:

• Dense retinal whitening
• Usually follows blood vessels
• Haemorrhage may be present

Management in HIV patients involves high dose antiviral medications, including:

• Ganciclovir (preferred initial treatment option)
• Valganciclovir
• Foscarnet
• Cidofovir

Induction therapy is followed by maintenance therapy. Patients should be started on antiretroviral therapy in addition.

Gastrointestinal complications of HIV/AIDS

Oral and oesophageal presentations

Oral lesions are early indicators of infection and can predict progression to AIDS. There are numerous lesions seen in HIV affecting the oral cavity, including:

• Oral hairy leukoplakia
• Pseudomembranous candidiasis
• Herpes simplex infection
• Kaposi’s sarcoma
• Ulcers, including aphthous ulcers

Oral candidiasis is usually caused by Candida albicans and is very common in HIV-l, affecting 80-90% of patients. ~15 species cause candidiasis, and in HIV is caused more commonly by C. dubliniensis relative to other patients. Oral candidiasis infection usually starts on the dorsum of the tongue. Pseudomembranous candidiasis is the common ‘thrush’ pattern of Candida infection. It features white-yellow plaques in the oral mucosa, which show an erythematous base when scraped off. Other risk factors for candidiasis include steroids, smoking, dentures, and poor saliva production. Management of oral candidiasis in HIV is with oral fluconazole, advice on hygiene and smoking cessation.

Oesophageal candida infection is more specific for HIV, affecting 10% of patients with HIV, usually at CD4+ T cell counts <100/μL. Symptoms include:

• Painful swallowing
• Difficulty swallowing
• Retrosternal pain
• Abdominal pain
• Asymptomatic finding

Differentials include viral oesophagitis, and so diagnosis requires visualisation (i.e. endoscopy) and histology (biopsy or brushing the oesophageal mucosa). An alternative is radiological examination with barium swallow – a ‘double swallow’ is needed and is about 90% sensitive. Management involves antifungal therapy with fluconazole PO or IV if swallowing is not possible, it is taken for 2-3 weeks.

Oral hairy leukoplakia is more specifically associated with immunosuppression, usually by HIV. It is caused by Epstein-Barr virus (EBV) and characteristically causes a white lesion on one side of the tongue. It is ‘shaggy’ in appearance, usually unilateral, and cannot be rubbed off. Over 90% of the adult population has EBV. It is treated with topical antiviral agents, which are generally effective and safe. Treatment options include:

• Combined 25% podophyllin and 5% acyclovir cream
• Gentain violet 2%
• Surgical excision
• Cryotherapy

Overall, the clinical significance of oral hairy leukoplakia is primarily as an indicator of progression towards AIDS, and its development should prompt testing if there is no HIV diagnosis.

Biliary and pancreatic presentations

HIV causes inflammation of the liver parenchyma and biliary tree. HIV additionally causes biliary tree damage by opportunistic infections, resulting in the formation of biliary strictures, which is termed ‘AIDS cholangiopathy’ and tends to develop with a CD4+ T-cell count <100/μL. The most common organisms causing AIDS cholangiopathy are:

• Cryptosporidium parvum
• Cytomegalovirus
• Microsporidia (usually Enterocytozoon bieneusi)

The presentation of AIDS cholangiopathy includes:

• Right upper quadrant pain
• Fever
• Jaundice
• Nausea and vomiting

Abdominal tenderness and hepatomegaly may be seen on examination. Blood tests demonstrate raised liver function tests with obstructive pattern. Imaging is often useful for establishing the cause of biliary symptoms in HIV:

• Ultrasonography is abnormal in ~75%, showing dilated intrahepatic and extrahepatic ducts and/or dilated CBD
• CT is not the preferred imaging modality but may demonstrate intrahepatic and extrahepatic dilatation
• Magnetic resonance cholangiopancreatography (MRCP) is preferred to ERCP due to lower risk of perforation and pancreatitis

AIDS cholangiopathy management involves:

• Endoscopic sphincterotomy
• Analgesia, e.g. a CT-guided coeliac plexus block
• Ursodeoxycholic acid improves deranged liver function
• Screening for cholangiocarcinoma

The liver parenchymal cells are injured by numerous mechanisms, including:

• Oxidative stress
• Lipotoxicity
• Metabolite accumulation
• Translocation of the gut microbiota
• The accumulation of toxic metabolites

Additionally, there may be indirect mechanisms which result in HIV causing liver injury or a higher risk of liver injury. These include:

• Hepatitis co-infection
• HIV-associated neoplasm
• Hepatotoxic antiretroviral therapy

Overall, these mechanisms and confounding factors (e.g. non-alcoholic fatty liver disease) mean that people with HIV are ~10 times more likely to die from liver infection than the population as a whole.

Transient elastography can determine the degree of liver fibrosis. Patients with higher viral load usually have higher levels of fibrosis. Despite hepatotoxicity associated with some antiretroviral agents, better controlled HIV and higher antiretroviral use is associated with a lower risk of fibrosis overall.

Dermatological complications

Skin conditions in HIV

HIV causes skin disease chiefly through the dysfunction of immune cells usually active in the skin which ordinarily reduce skin disease. In addition to loss of CD4+ T-cells, HIV causes:

• Fewer Langerhans cells
• Fewer macrocytes and monocytes
• Fewer NK cells

This causes fewer antigens to be presented, resulting in a range of skin conditions:

• Xerosis results from problems in the microcirculation leading to loss of oils in the skin and dryness, and is very common in HIV
• Atrophic dermatitis – common in the population but more frequent in persons with HIV
• Psoriasis – this is more frequent and has a different pattern than in seronegative individuals, with more extensive lesions, more frequent psoriatic arthritis and more acral lesions (affecting the hands and feet) than in seronegative individuals. An inverse pattern (affecting skin folds) is also more commonly seen.

Skin infections in HIV

Infection of the skin is more common in HIV than in seronegative people. The most frequent infections include:

HIV/AIDS associated malignancy

Kaposi’s sarcoma

Kaposi’s sarcoma is an angioproliferative neoplasm classically seen on the lower limbs of mostly elderly men, predominantly of Mediterranean extraction, however, is many orders of magnitude more frequent in patients with immunosuppression due to HIV or iatrogenic immunosuppression. It is caused by the Kaposi’s sarcoma herpes virus, which establishes lifelong latency. Kaposi’s sarcoma is much more common in men who have sex with men, even in the absence of HIV, and it is also more common in Sub-Saharan Africa. It is less frequent among patients on antiretroviral treatment.

Key features on presentation:

• Skin lesions – multiple pigmented lesions, often following Langer lines, raised or flat, with pink to purple colouration
• Oral lesions are more common in HIV, often nodular lesions within the oral mucosa
• Lymphadenopathy is more common in children and teenagers
• The tumour may spread to the lungs and gastrointestinal tract if HIV-related Kaposi’s sarcoma is left untreated

Diagnosis is often clinical, but biopsy for histological confirmation with diagnosis is recommended.
Management of Kaposi’s sarcoma in the context of HIV is with antiretroviral therapy. Other treatment depends on the stage of the cancer:

• T0 cancer can be managed with antiretroviral therapy
• In more advanced cancer, liposomal anthracycline therapy with doxorubicin or daunorubicin should be given alongside antiretroviral therapy
• Surgery can be used for symptoms or to control local growth

Prognosis is poorer in older patients and the presence of the human herpes virus.

Non-Hodgkin’s lymphoma

People living with HIV are at 100 times greater risk of developing Non-Hodgkin’s Lymphoma (NHL) than the general population. In the context of known HIV infection, non-Hodgkin’s lymphoma is an AIDS-defining malignancy, with 1 in 5 people with HIV developing this. Patients with AIDS-related lymphoma are more likely to develop high-grade B-cell lymphomas. The development of AIDS-related lymphoma is likely due to a combination of mechanisms:

• Loss of immunity, especially of antigen presentation cells
• Cytokine release causing B-cell activation
• Infection including EBV and human herpes virus-8
• HIV gene products (e.g. Tat) are oncogenic within B-cells

Risk factors for non-Hodgkin lymphoma in HIV include:

• Lower CD4+ T-cell count and higher HIV viral load
• Increased age
• Male sex
• Epstein-Barr virus exposure increases the risk for aggressive B-cell non-Hodgkin lymphoma.

People with HIV are more likely to present with more advanced non-Hodgkin lymphoma than other patients, with involvement of more distant sites.

Presenting features may include systemic ‘B-symptom’ type features:

• Fevers
• Night sweats
• Weight loss

Examination will likewise demonstrate clinical features in keeping with haematological malignancy:

• Splenomegaly or hepatosplenomegaly
• Rash
• Lymphadenopathy

Management is related to the cell type of the cancer involved:

• AIDS-related lymphoma is managed with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)
• Methotrexate may be given in addition
• Rituximab-based chemotherapy regimens may also be used
• Burkitt’s lymphoma is also treated with chemotherapy

Prognosis is generally poor, with relapse common. HAART improves outcomes with this condition.

Antiretroviral therapy

There are several objectives to antiretroviral therapy, including prevention of the mortality and morbidity from chronic HIV, and the prevention of people acquiring HIV infection, either in the form of pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP).

Antiretroviral medications

There are five classes of antiretroviral medications used in HIV, which act on different parts of the HIV life cycle:

• Entry inhibitors (EI) – maraviroc blocks the CCR5 receptor to reduce viral entry to cells.
• Integrase inhibitors (II) – raltegravir, elvitegravir and dolutegravir inhibit the integrase enzyme which prevents the viral DNA from being joined to the host DNA.
• Protease inhibitors (PI) such as atazanavir, darunavir, ritonavir, lopinavir and fosamprenavir block the protease enzyme needed to form mature virions.
• Nucleoside reverse transcriptase inhibitors (NRTI) such as tenofovir, lamivudine, emtricitabine, abacavir and zidovudine act by replacing a nucleoside causing termination of DNA production from RNA by viral reverse transcriptase.
• Non-nucleoside reverse transcriptase inhibitors (NNRTI) such as efavirenz, etravirine, nevirapine and rilpivirine also act to inhibit reverse transcriptase.

The current recommendations for ‘therapy naïve’ adults with newly diagnosed HIV involve:

• NRTI ‘backbone’ with tenofovir and emtricitabine.
• A third agent – atazanavir/darunavir, dolutegravir, elvitegravir, raltegravir or rilpivirine (elvitegravir and rilpivirine are recommended only in circumstances of poor renal function and raised viral load, respectively).
• An alternative to the NRTI ‘backbone’ is abacavir and lamivudine, which are recommended only if there is a sufficient viral load and in HLA-B57:01 negative individuals.
• Patients are recommended to be started on antiretroviral therapy as soon as they are diagnosed with HIV.

Pre-exposure prophylaxis

The most common PrEP regimen is tenofovir with emtricitabine. The following groups are currently recommended to have PrEP after consideration of risk assessment in conjunction with tertiary sexual health services:

• Men who have sex with men who are assessed to have high risk and have had recent ongoing condomless anal sex (i.e. within the previous six months).
• People who are having condomless sex with a partner who is HIV positive, unless the partner has been on ART for >6 months and has a viral load lower than 200 copies/mL.
• Others who on sexual history and medical history are assessed to have an increased risk of HIV otherwise.

PrEP is given with different dosing regimens can be considered in different patients:

• Daily dosing for insertive and receptive anal and vaginal sex
• On-demand dosing (4 or more tablets around sexual activity) for people involved in anal sex
• Intermittent dosing (4 or more tablets prior to and after sex) for people involved in anal sex

Post-exposure prophylaxis

PEP should be given to people who find themselves in the following circumstances:

• After receptive anal intercourse with a partner of unknown or positive HIV status unless undetectable viral load. (Considered following insertive anal intercourse under these circumstances).
• After receptive vaginal intercourse with a partner of unknown or positive HIV status unless undetectable viral load. (Considered following insertive vaginal intercourse under these circumstances).
• After a sharps or mucosal splash injury in the workplace with a person known to be HIV positive unless viral load is undetectable.

The first-line treatment for PEP is tenofovir disoproxil/emtricitabine and raltegravir. In pregnancy, raltegravir only is given twice daily in addition to tenofovir disoproxil and emtricitabine. The duration of PEP is generally 28 days.