AIDS

NATURAL HISTORY AND CLINICAL FEATURES

Natural history of HIV/AIDS Penny Lewthwaite Ed Wilkins

AIDS was first recognized in 1981 and is caused by HIV-1. HIV-2 causes a similar illness, but is less aggressive and restricted mainly to West Africa. Continuous high-level HIV replication leads to virus-mediated and immune-mediated destruction of the key immune effector cell, the CD4 lymphocyte. Two decades of study of the pandemic have provided a wealth of information about the natural history of HIV, leading to the development of highly active antiretroviral therapy (HAART), which has radically improved the prognosis. HIV-1 and HIV-2 – HIV-1 can be divided into different groups (M, O and N) and genetic subtypes. Group M strains account for the HIV epidemic and have 11 subtypes (A–K). Each of these tends to be associated with a particular geographical area, with less strong associations with transmission categories and resistance patterns. Subtype B is most prevalent in the Americas, Japan, Australia, the Caribbean and Europe. HIV-2 infection differs from HIV-1 in that patients have lower viral loads, slower CD4 decline, lower rates of vertical transmission and slower progression to AIDS (12-fold lower). It is important to distinguish between HIV-1 and HIV-2, because HIV-2 is inherently resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Epidemiology HIV affects 40 million individuals worldwide, with 4.9 million new cases and 3.1 million deaths estimated by the WHO in 2004. Sub-Saharan Africa has the greatest burden of disease, with an estimated 26 million infected individuals. In Southern African countries, 25–40% of adults are infected; the prevalence is 5–15% in most other Sub-Saharan countries. South Africa now accounts for one-third of deaths worldwide. In the UK, 6600 new cases were reported to the Health Protection Agency in 2003; the prevalence was estimated at 53,000, using population estimates and anonymous linked testing. Worldwide, the major route of transmission (> 75%) is heterosexual. About 5–10% of new HIV infections are in children and

Penny Lewthwaite is Specialist Registrar in Infectious Diseases, Tropical Medicine and General Internal Medicine at North Manchester General Hospital, Manchester, UK. Conflict of interests: none declared. Ed Wilkins is Consultant in and Clinical Director of Infectious Diseases at North Manchester General Hospital, Manchester, UK. His research interests include the toxicity of HIV antiretroviral drugs, hepatitis co-infection, and the investigation of treatment strategies. Conflict of interests: none declared.

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more than 90% of these are infected during pregnancy, birth or breast-feeding. Most of these cases occur in Africa, the Caribbean or South East Asia, but heterosexual transmission is also the most common mode of transmission in industrialized nations; racial and ethnic minorities represent an increasing proportion of cases. The incidence in injecting drug-users varies widely between countries. It is relatively low in the UK (< 1%), but may be up to 50% in other areas (e.g. Eastern Europe, Vietnam, north-east India, China).

severe and may be associated with an opportunistic infection (e.g. pneumocystis pneumonia, oesophageal candidiasis) as the CD4 count transiently declines below 200/µl. Neurological problems such as Guillain–Barré syndrome and Bell’s palsy may occur at this stage. Those with more severe symptoms are more likely to undergo rapid disease progression. Asymptomatic disease (Centers for Disease Control (CDC) category A disease) After seroconversion, the CD4 count usually increases again, but usually to a level below normal. Patients with CD4 counts of 350–800/µl are usually well. The viral load stabilizes at a set-point. The time before late-stage disease or AIDS develops varies. • In some individuals, CD4 count declines rapidly over the following 6–12 months. This usually indicates that the viral strain is using the CXCR4 rather than the CCR5 receptor. • In most cases, CD4 count declines slowly over 6–8 years. • In 5–10% of individuals (termed ‘long-term non-progressors’), CD4 count remains stable and viral load relatively low for many years or even decades. In a few cases, viral or host factors explain the slow progression; in most, however, the cause is unknown. Infected individuals may be completely asymptomatic or may have persistent generalized lymphadenopathy (defined as enlarged glands at two or more extra-inguinal sites). This is usually symmetrical, affecting cervical, axillary and inguinal nodes, but is usually mild and may not be noticed by the individual.

Natural history Infection HIV can be transmitted through blood, bodily fluids, sexual contact or breast milk. About 4–6 weeks after infection, the individual starts to develop antibodies to HIV. At an earlier stage, HIV is detectable in the plasma by nucleic amplification or p24 antigen. Most infected individuals seroconvert by 3 months and are HIV antibody positive; rarely, this takes up to 6 months. With the advent of antiretroviral drugs, the prognosis has changed dramatically; there is a potential for normal or nearnormal life expectancy, particularly when the diagnosis is made before HIV-related complications occur. The prognosis is less good in those presenting later, with a CD4 count of less than 200/µl, but is improving as knowledge of the disease increases and drug therapies improve. In 10–15% of cases, however, drug-resistant HIV is transmitted, and occasional strains are resistant to all three major classes of antiretroviral drugs. In many cases, resistant virus has a lower replication capacity than wild-type virus, but certain factors can reverse this.

CD4 count 200–350/µl (CDC category B disease) Without therapy, the CD4 count eventually declines. At a count of 350/µl, the individual becomes increasingly susceptible to pathogens such as Mycobacterium tuberculosis, Streptococcus pneumoniae and varicella-zoster virus (Figure 2). In a young patient, shingles is a sensitive marker of HIV infection. Tuberculosis (TB) is a particular hazard in patients with HIV infection, who are at greater risk of: • reactivation of latent infection (7–10% annual risk, compared with 5–10% lifetime risk in HIV-uninfected individuals) • acquiring TB from a contact (10–20%, compared with 5–10%) • developing progressive primary disease (30–40%, compared with 5–10%) • developing disseminated, miliary or extrapulmonary disease (> 60%, compared with < 25%). Patients are also at risk of second episodes of TB from exogenous infection, as demonstrated by isolate typing. The risk of TB depends on its prevalence in the community and whether the individual is latently infected with M. tuberculosis. Any HIV patient with symptoms of cough, weight loss and night sweats should be investigated for TB; radiological appearances may be atypical with advancing immunosuppression. Treatment is as in HIV-negative patients, with quadruple initial therapy followed by rifampicin and isoniazid, completed in 6 months in total. Pneumococcal pneumonia can occur at any CD4 count and is more often bacteraemic and recurrent. Recurrent oral and vaginal candidiasis invariably becomes a problem as the CD4 count approaches 200/µl. The finding of oral candidiasis without a history of inhaled corticosteroid use or antibiotics should suggest a diagnosis of HIV. First-line treatment is fluconazole.

Seroconversion Seroconversion illness occurs in 40–90% of infected individuals as a consequence of high levels of circulating HIV-1 and the immune system response (Figure 1). The most common symptoms are fever (80%), malaise (68%), arthralgia (54%), maculopapular rash (51%), myalgia, oral ulcers and pharyngitis. Most symptoms resolve after 7–10 days. In a few patients, the illness is more

HIV viral load and CD4 count

CD4 count

HIV plasma viral load

Symptoms Months

Symptoms Years

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Features of HIV infection with declining CD4 count CD4 count 200–350/µl • Pulmonary tuberculosis • Herpes zoster • Oropharyngeal candidiasis • Oral hairy leucoplakia • Salmonellosis • Kaposi’s sarcoma • HIV-associated idiopathic thrombocytopenic purpura • Cervical intraepithelial neoplasia II–III • Lymphoid interstitial pneumonitis CD4 count < 200/µl • Pneumocystis jirovecii pneumonia • Mucocutaneous herpes simplex • Cryptosporidium infection • Microsporidium infection • Oesophageal candidiasis • Miliary/extrapulmonary tuberculosis • HIV-associated wasting • Peripheral neuropathy

3 Chest radiograph in pneumocystis pneumonia.

lesions are identified on CT or MRI. The absence of IgG antibodies is suggestive of an alternative cause. First-line therapy is with sulfadiazine and pyrimethamine. Cerebral toxoplasmosis is prevented by co-trimoxazole prophylaxis, and those who are seronegative should be advised not to handle cat litter or eat undercooked meat. Kaposi’s sarcoma (Figure 4) is the most common malignancy associated with HIV. It is caused by human herpesvirus 8. Patients present with discrete, non-pruritic, non-tender, pink-purple papules that are often arranged symmetrically and develop on crease lines. Significant oedema from lymphatic involvement can occur and may precede the cutaneous lesions. The disease may be indolent or fulminant, with rapid visceral involvement and clinical deterioration; this is more likely at lower CD4 counts. Visceral disease can occur systemically in the lungs, the gastrointestinal tract and the lymphoreticular system. Palatal Kaposi’s is strongly suggestive of systemic disease. HAART and local therapy (radiotherapy or intralesional chemotherapy) is often curative in limited or localized cutaneous disease. In systemic disease, chemotherapy with liposomal doxorubicin or paclitaxel is required in addition to HAART. Oesophageal candidiasis causing pain and difficulty on swallowing can be a problem at this stage. Treatment is with flucon-

CD4 count < 100/µl • Cerebral toxoplasmosis • Cryptococcal meningitis • Primary CNS lymphoma • Non-Hodgkin’s lymphoma • HIV-associated dementia • Progressive multifocal leucoencephalopathy • Cytomegalovirus retinitis/gastrointestinal disease • Disseminated Mycobacterium avium intracellulare

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Oral hairy leucoplakia may occur; this appears as white corrugations on the side of the tongue and is caused by Epstein–Barr virus. It is usually asymptomatic and highly suggestive of HIV infection. Treatment is seldom required. CD4 count < 200/µl (CDC category C disease) As the CD4 count continues to decline, opportunistic infections and HIV-related tumours may develop (Figure 2). Pneumocystis jirovecii (formerly known as P. carinii) pneumonia (Figure 3) commonly presents in patients with a CD4 count of less than 200/µl. Before the advent of HAART, it caused significant mortality; this was reduced only by the introduction of primary prophylaxis in those with CD4 counts of less than 200/µl. Patients usually present with a 2–3-week history of dry cough, fever and disproportionate breathlessness. Co-trimoxazole is the agent of choice for prophylaxis and treatment. Alternative treatments include parenteral pentamidine, or clindamycin and primaquine; corticosteroids should be given for moderate-to-severe disease. Cerebral toxoplasmosis – in more than 90% of cases, cerebral toxoplasmosis is caused by reactivation of latent infection. Patients present with a 2–3-week history of fever, headache and seizures, with localizing signs on examination. Multiple ring-enhancing

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4 Kaposi’s sarcoma.

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azole. In patients who fail to respond, alternative diagnoses such as cytomegalovirus and herpes simplex oesophagitis should be considered. Diarrhoeal disease occurs at all stages of HIV infection and can be causd by various pathogens. Cryptosporidium parvum is a zoonotic intestinal parasite causing self-limiting diarrhoeal illness in HIV-negative patients and in those with CD4 counts of more than 200/µl. Chronic diarrhoea leading to weight loss and malabsorption may occur in patients with significant immunodeficiency. Microsporidium causes a less severe but similar illness. Together, these two organisms account for about 20% of cases of diarrhoea. Resolution is best achieved with HAART and reconstitution of the immune system to a CD4 count of more than 200/µl. Cytomegalovirus may affect the whole bowel, but most commonly causes inflammatory colitis associated with bloody diarrhoea.

AIDS-defining conditions • Oesophageal candidiasis • Cryptococcal meningitis • Chronic cryptosporidial diarrhoea • Cytomegalovirus retinitis • Chronic mucocutaneous herpes simplex • Disseminated Mycobacterium avium intracellulare • Miliary or extrapulmonary tuberculosis • Pneumocystis jirovecii pneumonia • Progressive multifocal leucoencephalopthy • Recurrent non-typhi Salmonella septicaemia • Cerebral toxoplasmosis • Kaposi’s sarcoma

CD4 count < 100/µl (Figure 2) Disseminated Mycobacterium avium intracellulare infection may be a problem as the CD4 count declines. Presentation is with fevers, weight loss, hepatosplenomegaly and anaemia. The diagnosis is usually made on mycobacterial blood culture, and treatment is with four agents (usually rifabutin, azithromycin, ethambutol and ciprofloxacin) for a prolonged period. On completing therapy, if the CD4 count remains less than 100/µl, secondary prophylaxis with weekly azithromycin should be used. Once HAART is initiated and the CD4 count reaches 100/µl, secondary prophylaxis can be stopped. Systemic fungal infection may occur in those with advanced disease. In the UK, the most common is Cryptococcus neoformans, which usually causes meningitis but can cause skin lesions and pneumonia. In patients from South East Asia, Penicillium marneffei is the second most common AIDS-defining diagnosis, whereas in those from the Southern USA and South America disseminated infection with Histoplasma capsulatum may occur. Cytomegalovirus infection often represents reactivation of latent disease. It has various presentations; retinitis and colitis are most common. Diagnosis involves histology (showing the characteristic owl’s-eye inclusion bodies), viral culture, IgM serology or polymerase chain reaction analysis. Treatment is with intravenous ganciclovir, cidofovir or oral valganciclovir. Neurological problems at CD4 counts of less than 100/µl include progressive multifocal leucoencephalopathy caused by JC virus, primary CNS lymphoma, and HIV encephalopathy leading to AIDS dementia. High-grade B cell non-Hodgkin’s lymphoma is 100 times more common in HIV-infected individuals than in the non-infected population. It is most common in those with CD4 counts of less than 100/µl and more likely to present with extranodal disease. There are several histological types. Treatment is with systemic chemotherapy.

• Non-Hodgkin’s lymphoma • Primary cerebral lymphoma • HIV-associated wasting • HIV-associated dementia

5 Facial lipoatrophy.

HAART usually comprises two NRTIs combined with one NNRTI or one ritonavir-boosted protease inhibitor. All of these agents have side-effects, including an increased risk of cardiovascular disease. As a result, lifestyle factors such as nutrition, smoking, immunizations, exercise, diet and sleep are becoming increasingly important.

Lipodystrophy Lipodystrophy is estimated to occur in 30–50% of HIV-infected patients. Clinical features include loss of subcutaneous fat (lipoatrophy) from the face (Figure 5) and limbs, and increased fat deposition in the trunk (central obesity). The cause is multifactorial, with contributions from HIV, genetic factors and anti-HIV drugs, particularly protease inhibitors. Mitochondrial toxicity (mainly NRTI-related) and insulin resistance (mainly protease inhibitor-related) are the two most important underlying events. Lipid abnormalities include hypertriglyceridaemia, hypercholesterolaemia, increased free fatty acids and reduced high-density lipoprotein. 

Highly active antiretroviral therapy HAART with three or more drugs has improved life expectancy and prognosis in patients with HIV infection. Since its introduction, there has been an 80% decrease in mortality in industrialized nations. There are three major classes of drugs – nucleoside reverse transcriptase inhibitors (NRTIs), NNRTIs and protease inhibitors.

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