Human immunodeficiency virus (HIV)
What is HIV?
The human immunodeficiency viruses (HIV) are two species of Lentivirus (a subgroup of retrovirus) that infect humans. Unlike most other viruses, HIV particles infect immune system cells, primarily CD4 helper T cells. The HIV virus spreads through bodily fluid exchange, typically during intercourse. Over time (often up to seven years without therapy), the number of CD4 helper T cells drops so low that they are almost undetectable in the blood, weakening the immune response to infection from other pathogens. This is what makes untreated HIV lead to acquired immunodeficiency syndrome (AIDS). Without the CD4 helper T cells, a simple cold or bacterial infection can be fatal.
Though people living with HIV tend to be most infectious in the first few months after being infected, many are unaware of their status until the later stages. People can go years(!) without knowing they are infected. Children may have more rapid disease progression and accelerated damage of the developing immune system compared to adults, with higher viral loads and less effective immunological responses to HIV infection than adults.
An HIV-positive person today who is on effective treatment can live as long and be as healthy as a person who does not have HIV. With treatment, the viral load in patients can be reduced and maintained at such a low level that the risk of transmitting the virus to someone else can be almost eliminated. However, it is a life-long infection as it’s impossible to clear it from your system, even when treated with drugs that target the virus. Without treatment, the average survival time after infection with HIV is estimated to be 9–11 years, depending on the HIV subtype.
Subtypes
HIV subtypes have distinct genetic differences and are associated with different epidemiological patterns and clinical characteristics. Mutations in the viral genome occur randomly when the virus replicates, with a mutation rate of ~1 nucleotide mutation per replicative cycle. Many HIV variants are simultaneously present in each infected individual, called “quasispecies”.
The two main HIV subtypes are:
HIV-1
HIV-1 is a rapidly replicating virus with an error-prone Reverse Transcriptase (RT). HIV-1 viruses can be further stratified into groups M, N, O, and P. Among these, HIV-1 group M viruses are the most prevalent, infecting nearly 90% of people living with HIV (“M” for “major”). HIV-1 infection results in chronic activation of the immune system and a subsequent gradual loss of CD4+ T cells, eventually leading to AIDS.
HIV-2
HIV-2 viruses are generally considered to be less virulent and less transmissible than HIV-1 M group viruses, although HIV-2 is also known to cause AIDS still.
What are the symptoms?
Not everyone reacts the same way to an infection of HIV, and symptoms may initially be subtle.
HIV is like many other viruses in that the initial symptoms are flu-like. As the infection progresses, more signs and symptoms might develop. This may include:
- Fever 🤒
- Swollen lymph nodes 💥
- Headache 🤕💥
- Sore throat 😮💨💥
- Rash 😳
- Fatigue 😩
- Weight loss 📉
- Diarrhea 💩
- Cough 😮💨
The immune system then kicks in, and the symptoms go away—so it can be easy to miss.
Diagnosis
Rapid diagnostic tests that provide same-day results are used. Most widely used HIV diagnostic tests detect antibodies produced by a person as part of their immune response to fight HIV. In most cases, people develop antibodies to HIV within 28 days of infection. During this time, people are in the so-called “window period” when they have low levels of antibodies that many rapid tests cannot detect, but they may still transmit HIV to others. People who have had a recent high-risk exposure and test negative can have a further test after 28 days.
How can it be treated?
HIV can be prevented and treated with antiretroviral therapy (ART).
Resistance-associated mutations (RAMs) can rapidly be selected when there is selection pressure, such as too low a concentration of antiviral drugs. Often, resistance to drugs in a specific antiretroviral (ARV) class results in cross-resistance to other drugs in that same class.
One predictor of HIV-1 disease progression is the level of HIV-1 RNA in the blood (i.e., viral load). The aim of treatment of HIV-1 infection is, therefore, to suppress and subsequently maintain the HIV-1 viral load to levels that are at least below the limit of detection of most commonly used assays (50 copies/mL of blood).
Current ART options are combinations (or “cocktails”) consisting of at least three medications belonging to at least two types, or “classes”, of antiretroviral agents. There are eight classes of antiretroviral agents (ARVs) and over 30 individual drugs:
- Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
- Protease inhibitors (PIs)
- Integrase inhibitors (INIs)
- Fusion inhibitor
- CCR5 antagonist
- CD4 T lymphocyte (CD4) post-attachment inhibitor
- gp120 attachment inhibitor
There are also two drugs, ritonavir (RTV, J05AE03) and cobicistat (COBI, V03AX03), which can be used as PK-enhancers (“boosters”) to improve the PK profiles of PIs and the INI elvitegravir (J05AJ02).
Depending on the guidelines, initial treatment generally consists of two NRTIs and a third ARV, either an INI, an NNRTI, or a PI with a booster.
Clinical studies
The European Medicines Agency (EMA) guideline expects new antiretrovirals to be tested in randomized, double-blind trials in patients who have not had antiretroviral therapy and whose virus carries no resistance mutations (treatment-naive), in which the new drug or a comparator is given with an otherwise identical regimen, and these trials are expected to use a non-inferiority design. Suppressing viral replication is an established surrogate endpoint for clinical benefit. The primary endpoint is the proportion of patients with plasma HIV RNA below the lower limit of quantification of the assay at 48 weeks, a binary outcome. Patients should be stratified at least by baseline viral load and CD4 count, and the trial should include a representative proportion with a viral load of at least 100,000 copies/mL. The total study duration should be at least 2 years, to provide long-term safety and efficacy data. Earlier dose-finding studies give the new drug alone for a short time, normally 7 to 10 days, and use the mean change in HIV RNA from baseline, a continuous outcome, as the primary endpoint [1].
Clinical pharmacology studies
Because HIV is treated with combination regimens and patients are likely to take a range of other medicines, the initial drug-drug interaction studies should give priority to other HIV drugs, drugs for co-infections such as hepatitis B and C and invasive fungal and bacterial infections, including tuberculosis and related infections (mycobacterial disease), hormonal contraceptives, and drugs for high blood lipids (hyperlipidemia), acid reflux (gastroesophageal reflux) and substance dependence. Tuberculosis is frequent in people with HIV, so before trials start, particularly in regions where tuberculosis is common, it is crucial that the relevant interaction studies have been done, so that patients who need tuberculosis drugs during the trial can use them adequately [1].
References
- https://www.who.int/news-room/fact-sheets/detail/hiv-aids
- https://www.science.org.au/curious/people-medicine/hiv