Primary HIV and common HIV/AIDS clinical

presentations in the STI clinic setting

David Lewis FRCP(UK) PhDNational Institute for Communicable Diseases

National Health Laboratory ServiceJohannesburgSouth Africa

Natural history

Acute HIV Clinical latencyDecline in

immune functionAIDS

2 months 3-10 years

Antiretroviral drugsAntiretroviral drugs

Pathogenesis - I

• HIV transmission enhanced by pre-existing inflammation or breaks in the mucosal surface/skin

• HIV gp120 and gp41 interact with target cells using CD4, CCR5 or CXC4 receptors

• The HIV variants appearing in >90% of acute HIV infections use CCR5

• This may be due to selection by the innate immune response or more efficient outgrowth of CCR5-using populations in the mucosal tissues of new host

Pathogenesis - II

• Within 72 hours of transmission, local virus replication results in infection at the site of entry and the local LNs – infection systemic by end of first week

• By day 10, most extra lymhoid tissue CCR5+ CD4+ effector-memory T cells have been infected or interacted with HIV

• Viral infection and co-receptor dependent apoptosis produce a dramatic depletion of CCR5+ CD4+ effector-memory T cells between days 10-21 (most pronounced in gut)

• Massive viral replication produces peak levels of viraemia

Pathogenesis - III

• Long-lived HIV reservoirs established within first month

• Follicular dendritic cells trap and protect infectious HIV particles and CD4+ memory T cells integrate HIV DNA

• Latently infected cells only produce virus if activated – their 44 month lifespan is a barrier to HIV eradication

• Immune system hyperactivation may result in symptoms of the acute retroviral syndrome

• Immune hyperactivation may be sustained by systemic exposure to bacterial endotoxin following disruption of the gut mucosal immune integrity

Pathogenesis - IV

• Anti-HIV IgM detected 2-4 weeks after infection – ineffective antibodies as of low titre, low avidity and low affinity

• Reduction in viraemia may reflect (i) exhaustion of CCR5+ CD4+ target cells, and (ii) appearance of specific anti-HIV cytotoxic CD8+ T cells at mucosal sites

• HIV viral loads (VL) declines to attain lowest level by 10 weeks post-infection in both blood and genital secretions

• Some oscillations may occur but steady ‘VL set point’ set by 8-24 weeks

Pathogenesis - V

• Anti-HIV cytotoxic T cell responses broaden by targeting more HIV epitopes

• First neutralising antibodies against glycosylated epitopes in the HIV envelope appear at same time

• Viral diversity increases – neutralisation escape variants appear and HIV-specific antibody responses broaden

• Set point viraemia determined by both viral factors and host genetics (CCR5 expression levels, HLA types)

• Strong and broad cellular and humoral immune responses are associated with lower set-point viraemia and slower CD4+ T cell loss, immune collapse and clinical progression

The acute retroviral syndrome

• Approximately 2/3 patients have some symptoms – rest asymptomatic

• Onset of symptoms is usually abrupt after 10-14 day (range 5-35 days) incubation period

Common

Less common

Occasional

fever/malaise, anorexia/weight loss, myalgia/arthralgia

headache (+/- meningeal signs), pharyngitis (+/- tonsillar exudates)rash

diarrhoea, ulceration (oral, oesophageal, genital)

Physical examination

• Rash (face, trunk, palms, soles)

• Pharyngitis

• Generalised lymphadenopathy

• Ulceration (oral, vaginal or anal)

• Candidiasis (oral, vaginal)

• Cranial nerve palsies (especially CN VII)

• Radiculpathy

• Encephalopathy

• Guillain-Barré syndrome

• Aseptic meningitis

Laboratory findings

• General leucopenia with atypical lympocytosis

• CD4 lymphopenia

• Mild thrombocytopenia

• Abnormal LFTs

• Lymphocytic pleocytosis (CSF)

Resolution and prognosis

• Most symptoms and signs resolve within 2 weeks

• Malaise, diffuse lymphadenopathy and laboratory manifestations may persist for several months

• Cohort studies enrolling seroconverting patients have shown that both the number and the duration of acute retroviral symptoms independently increase the risk of disease progression

• Seroconverting patients with >14 day’s acute illness had a 78% risk of progressing to AIDS within 3 years vs. a 10% risk for asymptomatic seroconverters (Lindback et al., 1994)

Risk factors for acute HIV infection

• Traumatic sex

• Receptive anal intercourse

• Genital ulcer disease in patient and/or partner

• STIs causing urethral/vaginal discharge

• Transactional sex

• IV drug use

• Use of other recreational drugs and sildenafil citrate

• Multiple sexual partners

• Being uncircumcised

• Vaginal douching

• Occupational injuries

Diagnosis of acute HIV infection

Two types of results are required:

(1) Positive screening assay

- HIV RNA/DNA amplification- HIV p24 antigen- 4th generation EIA (p24 Ag- HIV Ab combo)

(2) Negative or indeterminate HIV antibody assay

For patients at risk of acute HIV but with negative HIV results, repeat testing at least 1 month or longer out from exposure

Detection of acute HIV with antibody-based assays

• Modern antibody assays are highly sensitive to the presence of low-level, immature IgM-class antibodies

• These assays become positive within 4 weeks of infection (e.g. Western blot assays, HIV rapid tests)

• Less sensitive “detuned” antibody tests can be used to supplement a positive standard antibody result when acute HIV infection is suspected – these assays have reduced affinity or avidity for early HIV antibodies

Detection of acute HIV with NAAT and antigen assays

• HIV RNA/DNA tests can become positive in the 2nd week of HIV infection – pooling may reduce costs for RNA assays

• Assays for viral core antigens (p24 Ag alone or with 4th generation EIAs) become positive 3-6 days after HIV NAATs

• Antigen assays are useful to diagnose acute HIV in symptomatic patients

• Antigen assays have 77-91% sensitivity for detecting acute HIV in lower-risk populations

Screening patients with symptoms and/or risk factors for acute HIV

• Up to 13% of patients with a plausible history and compatible symptoms may have acute HIV infection

• For most with acute retroviral symptoms, viral loads are >100,000 copies/ml – low viral loads raise issues of false positive results (up to 2.6% depending on assay)

• Perform HIV RNA and standard antibody assays – if both are positive, perform “detuned” antibody assay

• p24 Ag can substitute for RNA testing if unavailable

• Alternative approach is to screen with 4th generation EIA and confirm positive results with antibody only EIA reflex testing

Screening for acute HIV infection with routine HIV testing - pooling

• Cost and specificity are more important when screening lower risk patients

• Pooling relies on a group-testing approach using NAATs

• Individual sera contributing to any positive pool are then re-tested individually or in smaller pools using the NAAT assay

• In a roll-out in North Carolina, pooling strategy detected 23 acute HIV cases among 109,250 sera at additional cost of US$ 3.63 per HIV test – represented 4% of all HIV cases detected

Acute HIV treatment with ARVs: a window of opportunity?

• Acute HIV may represent a unique opportunity to change the course of disease

• Early treatment may provide short-term clinical improvements in those with severe acute retroviral symptoms and/or CD4 lymphopenia

• From an immunological perspective, early treatment may:

- limit the establishment of latent HIV reservoirs

- protect the developing host immune response by infection of HIV-specific CD4 cells

- reduce immune activation

- limit HIV diversification

Acute HIV treatment with ARVs: what is the evidence that it works?

• Two early studies of a 6 month course AZT vs. placebo in the treatment of acute retroviral syndrome showed, during 12-15 months of follow-up, that the AZT group had a lower prevalence of opportunistic infections and a greater rise in CD4

• Neither study showed a significant reduction in VL and long term follow up failed to show decreased progression to AIDS

• Subsequent trials/reports in the HAART era showed:

- stronger HIV-specific and sustained T cell responses

- decreased frequency of opportunistic infections

- reduced progression to AIDS

Initiation of continuous ARV therapy during acute HIV infection

• Prospective cohort study of 102 patient treated with HAART before seroconversion (acute) or within one year of seroconversion (early) (Kassutto et al., 2006)

• Most achieved sustained virological suppression by 3 months – still present at 18 months of follow-up

• Mean nadir CD4 was 422 – increased to 702 at the end of year 1 and continued to increase over 60 months in those continuing ARVs (higher than historical controls)

50% of patients discontinued ARVs due to side-effects

Initiation of short-term ARV therapy during acute HIV infection

• Short-term (discontinuous) ARV therapy for acute retroviral infection has met with mixed results

• Long-term benefits (18 months post cessation of therapy) more marked if ARVs started before seroconversion

• This may be due to the relative preservation of the integrity of the immune system and the resultant stronger HIV-specific response in those treated very early

• Further trials required to assess longer term benefits

Special considerations for early ARV therapy

• Prognostic value of VL or CD4 cell count before establishment of the viral set point highly questionable

• Prescribe co-trimoxazole as oral prophylaxis against Pneumocystis jiroveci pneumonia if CD4 < 200 cells/mm3

• Treat as early as possible, i.e. at the time of diagnosis

• Do not delay for adherence discussions, CD4/VL results, HIV genotyping results

• Give 3-4 drugs at start - modify based on HIV resistance genotyping results

• Given high NNRTI resistance levels, best to start with a PI-based regimen

Key messages regarding ARV treatment of acute HIV infection

• Theoretical reasons support early treatment

• Early benefits evident in trials in terms of CD4 count and disease progression – effect on VL and long term protection remain unclear

• Benefits highest for those with severe symptoms and marked decline in CD4 count

• Decision to treat must be carefully balanced: benefits vs. adverse reactions, metabolic effects, potential unknown long term toxicities, potential for drug resistance, high cost, adherence issues

• Approach should be adopted in specialist centres, ideally in research context

Sexual transmission of HIV

HIV viral burden in semen

Effect of biological intervention (theoretical)

Cohen MS and Pilcher CD, JID 2005;191:1391-1393

Example of diagnosis of acute HIV as a public health tool

• In April 2004, a male performer in the Los Angeles-based heterosexual adult film industry found to have acute HIV

• Industry agreed to a 1 month voluntary quarantine while other performers were tested

• 3 (23%) additional acute HIV infections were identified among 13 traced sexual contacts exposed in the 30 days before the index’s HIV RNA test became positive

• Intervention prevented any further HIV transmissions

• Patient-centred , individualised HIV risk reduction counselling is a key strategy in managing acute HIV cases