3 Human immune deficiency virus and AIDS
Introduction
• Acquired immuno-deficiency syndrome (AIDS) is characterized by infection with opportunistic organisms and malignancy. The onset of development of AIDS following HIV infection can range from months to years (the median incubation period is 10 years).
• Routes of acquisition. HIV can be isolated from many body fluids and tissues but the majority of infections are transmitted via semen, cervical secretions and blood.
• Sexual intercourse (vaginal and anal). Heterosexual intercourse accounts for most infections; circumcision reduces infection rates.
Pathogenesis
• HIV enters through the wet mucous membranes of the genital tract and infects CD4-bearing dendritic cells and macrophages, which transport the virus to the regional lymph nodes.
• Once in the draining lymph node, HIV particles are exposed to other cell types, including CD4-bearing T-helper cells.
• The adaptive immune system responds by the proliferation and activation of HIV-specific lymphocytes. HIV has a preference for infecting activated CD4 T-cells, which become depleted.
Disease manifestations of hiv infection
These can be due to HIV itself, to the treatment of HIV and lastly to immunosuppression, which leads to opportunistic infections (p. 111) and cancer (p. 117).
HIV infection
HIV-associated nephropathy (HIVAN)
• Initial management is as for presentation of acute kidney injury. Other reversible causes should be excluded. Co-infection with hepatitis viruses should be ruled out, as this can cause differing glomerular nephritides. Biopsy may be necessary to confirm the diagnosis.
• Treatment is with anti-retroviral medication, which usually produces a dramatic response; ACE inhibitors are also beneficial. Necessary supportive therapy, including dialysis, should be given whilst the response to the primary treatments is being assessed. Prednisolone appears to be beneficial in some patients.
HIV-associated dementia
• Treatment with highly active anti-retroviral therapy (HAART) is associated with an improvement in symptoms in over half the patients treated. Whether CNS penetration is essential for this effect is not clear. AZT has the most evidence of efficacy. Other anti-retrovirals that have good CNS penetration include abacavir and the non-nucleoside reverse transcriptor inhibitor (NNRTI) class of drugs (p. 94).
Manifestations due to treatment of HIV
Mitochondrial toxicity and lactic acidosis
• Mitochondria have their own genome, which utilizes the enzyme, γ-DNA polymerase, for replication. Unfortunately, γ-DNA polymerase, like viral reverse transcriptase, recognizes nucleotide reverse transcriptase inhibitors (NRTIs) as nucleosides, leading to chain termination and interruption of the mitochondrial life cycle.
• Organ damage occurs when sufficient mitochondria within a tissue are affected for normal function not to be maintained.
• Different NRTIs affect different organ systems preferentially. Mitochondrial toxicity can be seen affecting the peripheral nerves, pancreas, liver, muscle and bone marrow. Pancreatitis should be treated, but with medication stopped. Myopathy and peripheral neuropathy can improve with a change of medication.
• Liver toxicity can lead to the potentially fatal problem of lactic acidosis. Symptoms and signs of this are non-specific and include nausea, malaise, weight loss and abdominal pain. Investigations may show abnormal liver enzymes. A blood lactate measurement with ABG should be done. Specialist advice should be sought in any patient on NRTIs with an acidotic pH and a raised blood lactate.
Approach to the Patient
Initial diagnosis
In patients with undetermined/negative HIV serology, the diagnosis of an acute infection is by demonstrating a high viral load or a positive p. 24 antigen (which disappears after 8 weeks of infection).
Investigations and monitoring
Initial assessment
All clinicians should be of the competence necessary to obtain consent for an HIV test. The British HIV Association provides a list of associated presenting conditions for which an HIV test may be indicated (http://www.bhiva.org/cms1222621.asp). Many patients are diagnosed when they present themselves to a sexual health clinic.
• Take a history with details of route of transmission, probable length of time infected and any symptoms of seroconversion.
Box 3.1
(Based on British HIV Association guidelines 2008)
Baseline investigations in a newly diagnosed asymptomatic patient with HIV infection
A full examination, including fundoscopy, neurological examination and palpation of all lymph node groups, is carried out.
CD4 count
• Helper T-cells bearing the marker CD4 are infected with HIV. The absolute concentration of CD4 T-cells within blood has proven correlations with disease stage and risk of disease progression.
• Primary prophylaxis is indicated at CD4 counts below 200 to protect against Pneumocystis jiroveci, and below 100 to prevent toxoplasmosis.
• A good response to HAART correlates with a rise in the CD4 count, which is a good indication of the patient’s immune status.
• CD4 counts are performed every 3 months in asymptomatic patients (Box 3.1), but more frequently if unexpected changes are seen in either the clinical state or the viral load of the patient.
The viral load
• The viral load is an independent indicator of disease progression, i.e. the higher the viral load, the more likely the patient is going to progress to severe immunosuppression and AIDS.
• It can also be used as a marker of treatment success. HIV can only develop resistance if it is allowed to replicate actively whilst in the presence of the drug. Successful treatment is dependent on the prevention of resistant strains emerging. An aim of treatment is to reduce the viral load to below the level of detection within 3 months. Persistently detectable viral loads indicate ongoing viral replication and correlate with the development of resistance and treatment failure; they would usually warrant a change in the management of the patient. Thus, the viral load is used to assess:
Genotyping
• Genotype variations within HIV exist between viral subtypes and also point mutations associated with retroviral drug usage.
• Phenotype variations give an indication of possible drug resistance, although they do not detect low levels of resistant viruses (< 20% of viral populations).
• In the absence of medication, the dominant viral species will revert back to wild type relatively quickly.
• Delay in resistance testing once medication is stopped can lead to missing resistant mutants in a patient failing a drug regimen.
highly active anti-retroviral therapy (haart)
Available anti-retroviral medications, along with their side-effects, are shown in Table 3.1.
Available drugs
Nucleoside reverse transcriptase inhibitors (NRTIs)
• Zidovudine (AZT), when used as monotherapy, leads to resistant mutations appearing within the reverse transcriptase gene in months. A combined formulation with lamivudine (3TC), i.e. Combivir (AZT/3TC) has proven popular due to the decreased pill burden. Cross-resistance with other drugs in this class is a problem. Switching AZT to abacavir can reduce the rate of fat loss. The drug should not be used with D4T, as they antagonize each other’s effects. Bone marrow toxic effects can be increased by probenecid, ganciclovir, doxorubicin, co-trimoxazole, pyrimethamine and sulfadiazine.
• Stavudine (D4T) is a thymidine analogue like zidovudine. Its major problems with lipodystrophy and peripheral neuropathy have led to it becoming obsolete but it is still used in some countries. Specific mutations in the reverse transcriptase gene can confer cross-resistance between this drug and lamivudine (3TC), emtricitabine (FTC) and abacavir (ABC). Antagonistic interactions between AZT and D4T occur. Co-prescribing with other medications that are particularly neurotoxic is not advised.
• Abacavir (ABC) is a guanosine analogue that has a good side-effect profile in the majority of patients and crosses the blood–brain barrier. It is available in two combination pills: one as a triple combination with AZT and 3TC, and one as a combination with 3TC. It can be used once daily with 3TC. The triple nucleotide regime alone is now not recommended, as studies have called into doubt its effectiveness when compared with other NNRTI- or PI-based regimes. Hypersensitivity reactions are a major problem. If two differing hypersensitivity symptoms occur, stop the medication. In most cases, once stopped, the medication must never be restarted. In patients whose prescription for abacavir has been stopped for another reason, restarting the medication should be done with regular monitoring. Viral resistance to ABC occurs in a stepwise fashion, and the appearance of mutants with low-level resistance does not impede the drug’s efficacy. However, with the appearance of large numbers of AZT-associated mutations in the reverse transcriptase gene, the drug significantly loses potency.
• Lamivudine (3TC) is a popular cytosine analogue that is effective when used as part of an NNRTI- or PI-based combination regime. It can be given once daily. In general, the drug is well tolerated. Resistance to this medication develops rapidly, the commonest reverse transcriptase mutation occurring at codon 184 (M184V/I). This drug, as well as FTC, is effective in the treatment of hepatitis B.
• Didanosine (DDI) is effective as part of a combination regime in the treatment of HIV, and is available in once-daily or twice-daily formulations. Strict dietary restrictions (it must be taken 2 hours before or after food on an empty stomach) in its administration have clouded its common use (Table 3.1). The enteric-coated form is taken once daily but still has to be taken at least 2 hours before or 2 hours after any oral intake other than water. Given the number of other HIV medications that are recommended to be taken with food, this complicates the dosing regimen. The formulation contains calcium and magnesium antacids. There is evidence of cross-resistance with other NRTIs. It interacts with tenofovir, causing decreased levels of both.
• Emtricitabine (FTC) is a cytosine analogue that is active against both hepatitis B and HIV, though it is not currently recommended for the treatment of hepatitis B. It is available in a once-daily formulation and in a combination formulation with tenofovir. FTC has been compared with D4T and 3TC, and shows equivalence or improvement over the more established therapies. No studies have looked at possible interactions between FTC and other cytosine analogues (DDC and 3TC). However, with the evidence of competition between D4T and AZT, it is not recommended that they be co-prescribed. The mutation at codon 184 (M184V/I) of the reverse transcriptase gene that confers resistance to 3TC also confers resistance to FTC. The virus strains carrying this mutation are more susceptible to AZT.
