HIV overview

Brief introduction to HIV

Impaired immune function in people living with HIV is caused by ongoing infection and the destruction of lymphocyte CD4 T cells³. Early diagnosis is crucial in achieving virological control, which allows an effective immune function to be retained and reduces the direct and indirect inflammatory effects of viral replication on multiple organs^4,5. People with viral loads brought to undetectable levels by ART do not transmit HIV to others¹.

There are two main subtypes of HIV: HIV-1 and HIV-2. HIV-1 is the most widespread globally and is more virulent, accounting for around 95% of all HIV infections⁶. Unless otherwise specified, we refer to HIV-1 here. HIV is a lentivirus and belongs to the retrovirus family. HIV-1 is the most genetically diverse retrovirus due to its fast replication, high mutation rate and increased genetic recombination frequency^7,8.

HIV-1 is believed to have originated in the Democratic Republic of Congo around 1920 as a zoonosis, crossing from chimpanzees to humans⁹. The current global epidemic emerged as a newly recognised health condition in the early 1980s⁹. Prior to the availability of ART, HIV diagnosis led almost invariably to a fatal outcome³.

HIV symptoms and progression

Symptoms of HIV infection vary depending on the stage of infection¹⁰. During seroconversion (the period between the first infection and the development of antibodies to the virus), people who acquire the virus or are HIV-positive may more easily transmit the virus to others due to uncontrolled viral replication¹¹. Seroconversion may present with a flu-like illness (fever, sore throat, rash), which can vary in severity and may even be asymptomatic¹¹. Research has shown that symptomatic seroconversion occurs in at least half of individuals, though it may be observed in as many as 80–90% of HIV transmissions¹¹.

Before the availability of antiretroviral treatments for HIV, the progressive attack on the immune system caused by HIV infection most commonly led to immunodeficiency resulting in a variety of secondary opportunistic infections

The acute infection stage generally develops within 2–4 weeks of exposure¹². Without treatment, chronic HIV infection usually progresses to acquired immune deficiency syndrome (AIDS) within 10 years, although this can occur more rapidly in some people¹². Around 10–15% are rapid progressors (progress within ~2 years)¹³ and <1% are HIV controllers, individuals who maintain low viral loads despite the absence of ART¹⁴. HIV controllers may be classed as elite controllers or long-term non-progressors (LTNPs)^14,15. Elite controllers are those who maintain viral loads of <50 copies/mL¹⁴, while LTNP refers to those who maintain a CD4 cell count of >500 cells/mm³ over several years¹⁵.

Ongoing uncontrolled viral replication leads to the progressive weakening of the immune system. It can lead to the development of various symptoms, including weight loss, lymphadenopathy, fever, cough and the onset of infections and/or neoplastic processes^1,16.

Advanced HIV disease

AIDS is the most advanced stage of HIV infection¹. Late presenters are defined as persons presenting with a CD4 cell count of <350/mm³ or an AIDS-defining condition¹⁷. Advanced HIV is defined as a CD4 cell count of <200/mm³ (World Health Organization [WHO] stage 3 or 4)¹⁸. CD4 cell count is generally between 500 cells/mm³ and 1,500 cells/mm³ in healthy persons not living with HIV¹⁹. When the CD4 cell count drops below 200 cells/mm³, the immunity provided by CD4 T cells is no longer effective. If treatment is not undertaken or is unsuccessful, illnesses may develop due to impaired immune function, such as opportunistic infections and/or malignancies^16,19.

AIDS-defining illnesses include²⁰:

• multiple/recurrent bacterial infections
• candidiasis of bronchi, trachea, lungs or oesophagus
• disseminated or extrapulmonary coccidioidomycosis
• chronic intestinal cryptosporidiosis (>1 month)
• cytomegalovirus
• herpes simplex (chronic or bronchitis, pneumonitis or esophagitis)
• disseminated or extrapulmonary histoplasmosis
• Kaposi sarcoma
• lymphoma
• disseminated or extrapulmonary mycobacterium
• Mycobacterium tuberculosis
• Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia
• recurrent pneumonia
• progressive multifocal leukoencephalopathy
• Salmonella septicaemia
• toxoplasmosis of the brain
• wasting syndrome attributed to HIV

It is estimated globally that approximately 15% of people with HIV are unaware they are carrying the virus and undiagnosed cases account for almost 40% of all HIV transmissions²¹

Early diagnosis reduces the complications of HIV infection and decreases the risk of transmission¹.

Key biological markers for testing include HIV RNA, viral p24 antigen, HIV antibodies and CD4 cells²². HIV status is essential for diagnosis, disease monitoring and treatment effectiveness. In contrast to third-generation HIV tests, which only detected HIV antibodies, fourth-generation tests measure both HIV antibodies and p24 antigen²³. This allows these tests to identify the virus sooner. The p24 antigen is detectable as early as 11–15 days after exposure and is detectable for a few days before HIV antibodies develop^23,24. Fourth-generation tests are now recommended²³.

These tests have high sensitivity of at least 99.7% and specificity of at least 99.5%²³. It is difficult to define the ideal window for testing; however, it is estimated that for fourth-generation tests, that window is between 13 and 24 days, and 99% of people with HIV will have a positive test within 44 days of exposure²³.

Viral load in peripheral blood is a surrogate marker of viral replication rate. Effective treatment can reduce the viral load to undetectable levels²⁵.

Following earlier diagnostics identifying immune system reactions to HIV, current diagnosis and monitoring relies on assessments of viral load via tests for HIV RNA

Viral load is the preferred parameter for monitoring people on antiretroviral therapy (ART), as it is an early and accurate way of measuring treatment success²⁵. US and European guidelines recommend starting ART for all people with a diagnosis of HIV, irrespective of CD4 cell count^25,26.

HIV is transmitted through bodily fluids, including semen, vaginal and anal fluids, blood and breast milk, but not sweat, urine or saliva²⁷. There is extensive evidence that people with a stable undetectable viral load cannot transmit the virus, which is important in tackling the virus and the fight against stigma²⁷.

There are now seven approved classes of HIV drugs, which target different stages of the HIV lifecycle (Figure 1)²⁸.

Figure 1. HIV structure, lifecycle and key drug targets²⁹. gp, glycoprotein; mAb, monoclonal antibody; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor.

After infection, HIV envelope glycoproteins gp120 and gp41 attach to the CD4 lymphocyte, interacting with the primary receptor (CD4) and coreceptors CCR5 or CXCR4³⁰. This facilitates viral entry by triggering significant structural rearrangement and inducing membrane fusion³⁰.

Targeting the cell entry stage

There are different subclasses of drugs that target the cell entry stage of infection³¹.

Attachment inhibitors

Fostemsavir binds to the HIV gp120 envelope close to the gp120-CD4 binding site, preventing the structural change required for gp120 to attach to the CD4 receptor³¹.

CD4 post-attachment inhibitors

Ibalizumab is a humanised monoclonal antibody that binds to the domain 2 region of the human CD4 cell receptor. This binding does not prevent attachment of HIV gp120 with the host CD4 receptor but, through steric hindrance, it prevents the regular post-binding conformational changes in gp120 that are required for gp120-coreceptor binding³¹.

CCR5 coreceptor antagonists

Maraviroc binds to the host CCR5 coreceptor, changing the structure and hampering the binding of the V3 region of gp120 in the R5 strains of HIV³¹.

Fusion inhibitors

Enfuvirtide is a 36-amino-acid peptide that mimics the HR2 domain of the HIV gp41 HR2 domain and interferes with the normal HR1 and HR2 interaction, which is essential for the fusion of the viral and host membranes³².

Once fusion has occurred, the shell of the capsid disintegrates, and HIV reverse transcriptase transcribes the viral RNA into DNA. This DNA is transported across the nucleus, where viral protein integrase integrates into the host’s DNA. The host’s normal transcription machinery transcribes HIV DNA into multiple copies of new HIV RNA. Some of this RNA becomes the genome of a new virus, while the cell uses other copies to make new HIV proteins. The new viral RNA and HIV proteins move to the cell surface, where a new, immature HIV forms. Finally, the virus is released from the cell, and HIV protease cleaves newly synthesised polyproteins to create a mature infectious virus³³.

Targeting reverse transcriptase

Reverse transcriptase is responsible for converting viral RNA into proviral DNA³⁴. The enzyme is prone to error, and there is a high likelihood of transcription errors during HIV replication, translating to a high potential for many mutations to occur. This increases the chance of resistance to therapeutics and contributes to ineffective host immunity⁷.

Antiretroviral drugs targeting reverse transcriptase include:

• nucleoside reverse transcriptase inhibitors (NRTIs), which inhibit reverse transcriptase activity by integrating into the viral DNA, competing with the cell’s nucleosides and causing DNA chain termination³⁵
• non-nucleoside reverse transcriptase inhibitors (NNRTIs), which bind non-competitively to the reverse transcriptase enzyme to decrease its ability to act³⁵ 

Targeting HIV integrase

The HIV integrase enzyme acts to facilitate the insertion of viral genetic material into the DNA of the host cell³⁶.

Antiretroviral drugs targeting the integrase stage, known as integrase strand transfer/integrase inhibitors (INSTIS/INIs), block the integration of viral DNA into the DNA of the host CD4 cell, preventing HIV replication³⁷.

During the latency phase of the cell, HIV is dormant. Its genetic material now sits integrated within the nucleus, and it can be challenging to detect infected cells^38,39. Cell activation via antigens or cytokines leads to reactivation of the latent HIV provirus³⁹. Following activation, host cell RNA polymerase is recruited by the pro-virus to create further copies of the virus’s genetic material³⁸.

Targeting HIV protease

Viral protease cuts polyprotein precursor chains into active viral proteins⁴⁰. In this way, the protein components of new virus particles are ready to begin assembly³⁸.

Antiretroviral drugs targeting the protease stage are a key therapeutic strategy, as proteases play an essential role in viral maturation⁴⁰.

Targeting HIV capsid

Capsid is a protein shell that protects the genetic material of HIV and plays an important part in viral replication⁴¹.

Capsid inhibitors interfere with multiple stages of the HIV replication cycle via selective binding to the interface between capsid subunits⁴². As of June 2024, there is currently one capsid inhibitor approved in the USA and EU^41,43.

Prevention of HIV transmission

A substantial reduction in HIV incidence is required to meet the target of ending the epidemic by 2030, as defined in the Sustainable Development Goals⁴⁴. Reaching these targets requires a sustained focus on HIV prevention, including new interventions and approaches⁴⁴.

General preventive measures include the following⁴⁵:

• Correct and consistent use of condoms
• Access to sterile injecting needles and not sharing needles for individuals who inject drugs
• Availability of pre-exposure prophylaxis (PrEP)
• Treatment as prevention

Pre-exposure prophylaxis

The World Health Organization (WHO) recommends that people at substantial risk of HIV infection be offered tenofovir disoproxil fumarate-based oral PrEP as part of comprehensive prevention. Oral PrEP is highly effective at preventing HIV when used as directed⁴⁶.

In 2021, the WHO also recommended that the dapivirine ring may be offered as an additional prevention choice for women at substantial risk of HIV. In 2022, a recommendation for long-acting injectable cabotegravir was added⁴⁶.

Other products, such as multipurpose prevention products that combine antiretroviral drugs with contraception, are currently being studied as additional PrEP options⁴⁶.

Post-exposure prophylaxis

Post-exposure prophylaxis (PEP) must be initiated within 72 hours of exposure, but as soon as possible is advised. Treatment should be continued for 28 days⁴⁷.

For adults and adolescents, the preferred backbone regimen for HIV PEP is tenofovir disoproxil fumarate plus lamivudine or emtricitabine⁴⁸. Lopinavir/ritonavir or atazanavir/ritonavir is recommended as the preferred third drug⁴⁸. When available, raltegravir, darunavir/ritonavir or efavirenz may be considered as alternative third drug options⁴⁸.

Considerations in children

Zidovudine plus lamivudine is recommended as the preferred backbone regimen for children 10 years and younger⁴⁸. Abacavir plus lamivudine or tenofovir disoproxil fumarate plus lamivudine (or emtricitabine) can be considered as alternative regimens⁴⁸. Again, lopinavir/ritonavir is recommended as the preferred third drug⁴⁸. When available, atazanavir, darunavir and raltegravir may be considered as alternative third drug options⁴⁸.

Considerations in infants

Antiretroviral therapy should be initiated urgently among all pregnant and breastfeeding women living with HIV²⁶.

The WHO and US guidelines recommend prophylaxis in newborn infants with perinatal exposure to HIV. The WHO guidance advises co-trimoxazole prophylaxis until breastfeeding has ceased and HIV infection excluded, with lopinavir/ritonavir as the preferred third drug⁴⁸. The US recommendations vary between a two-drug and three-drug zidovudine-based regimen according to the level of HIV acquisition risk and whether the infant is born prematurely or at term⁴⁹.