Pharmacotherapy/Treatment Of Human Immunodeficiency Virus (HIV)

Human immunodeficiency virus (HIV) is a sexually transmitted infection (STI). It was first discovered and documented in 1981 among two groups in San Francisco and New York in the United States of America (USA).

Ever since then, more than 76 million people have been infected as of 2019. 33 million confirmed dead. There are currently 38 million people living with HIV as at 2019. HIV/AIDS in 2019 alone claimed the lives of 690000 people with 1.7 million new cases recorded.

Out of all HIV cases, two thirds live in Africa (25.7 million). 25.4 million infected persons have access to drugs (antiretroviral, ARV). The fight against HIV seems to be winning as the cases of new infection from 2000 to 2019 fell by 39 percent and 51 percent HIV related deaths.

HIV are retrovirus in the family, lentivirus genus. They are envelope diploid single-stranded, positive-sense ribonucleic acid (RNA) viruses with a deoxynucleic acid (DNA) intermediate which is an integrated viral genome (a provirus) that persists within the host DNA.

It targets the immune system. Immune system is a measure of CD4 cell counts. A normal CD4 cell level is above 500 cubic millimetres (mm³). It destroys immune cells and weakens the body's ability to fight infection and some types of cancer.

Read Also: Management of viral infections

Infected persons begin to fall ill to minor infection the body normally can fight off. It is the cause of acquired immunodeficiency disease syndrome (AIDS). AIDS is defined as a lower quantity of CD4 cell counts (less than 200 cubic millimetres), development of certain types of cancer or infection or other severe long term clinical manifestations.

Symptoms Of HIV

1. Swollen lymph node especially at the groin

2. Weight loss

3. Fever

4. Diarrhoea

5. Cough

6. Body rash

Symptoms Of AIDS

AIDS is the clinical manifestation of opportunistic infections. They are tuberculosis (TB), cryptococcal meningitis, cancer such as lymphoma and kaposi's sarcoma and other types of bacteria infection.

Mode Of Transmission

HIV is an infection of the blood and body fluid. Newly infected individuals are more contagious for the first few months than those who are at an advanced level. There are several ways blood and body fluids can be exchanged. The level of risk posed by each method varies.

1. Blood transfusion poses the greatest risk. About 3 percent of transfusion will lead to HIV infection due to poor screening.

3. Unprotected sex is one of the most common method of contracting HIV but not the most risky. This is because more people have sex than taking blood transfusion. However, unprotected sex with an infected person does not lead to automatic infection. There are situation that makes contracting HIV through sex high. They include highly rough sex. Sex is less than one percent risky. Unprotected sex include anal, oral and vaginal sex. Semen and vagina secretions are the main body fluid that lead to infection through sex. Blood is hardly involved. However, kissing with a fresh wound in both mouths can lead to infection.

4. Breastfeeding is another source of contracting HIV.

5. Sharing of sharp objects like razor and needles by family members and drug addicts is another means of contracting the virus. Using the same hair clippers with an infected person is risky, it is unlikely for such to happen. Although, sharing clippers is a common source of other infections.

A lot of people are always scared of HIV patients. The fear of contracting the virus and also facing the idea of death is not what they want to think about. For that reason, they fear doing anything with HIV patients. However, using the same cutlery, shaking hands, hugging, eating together, etc does not spread the virus to others.

Types Of HIV

There are two types of HIV. They are HIV 1 and HIV 2. They have multiple subtypes or clades. HIV 1 has a lower risk of transmission, slow progression to AIDS, lower viral load and is rare in the developing world. HIV 2 which is the opposite is more common in the developing society. Most of the drugs under researched by scientists in the developed society use strains easily available to them which is HIV type 1. This can be a problem for research into a suitable drug for the strains in the developing world. Co-infection is possible.

HIV infection
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Stages Of HIV

1. Stage one: infect the cell and quickly replicate in the body. Come with short flu-like symptoms like headache, fever, sore throat and a rash that appears within days to weeks. Seroconversion sets in due to immunity reaction developing antibodies. The CD8 cells and cytotoxic T cells start to attack the virus. A very few percentage of the world population successfully fight off the virus using CD8 cells and cytotoxic T cells. They are called long term non progressive.

2. Stage two: the first wave of symptoms subside lasting for anywhere between 2-10 years. They remain contagious.

3. Stage three: new symptoms appear with fatigue, weight loss, mouth ulcer, thrush and severe diarrhea. These are caused by opportunistic infection e.g toxoplasmosis, TB and kaposi sarcoma.

4. Stage four: full blown AIDS. They come down with severe symptoms from different infections.

Risk Factor

People who have some form of infection or disease that weaken the immune system are more at risk of contracting the virus from others. Some of such infections are syphilis, herpes, chlamydia, gonorrhea, bacterial vaginosis.

Diagnosis

There are several tests for HIV. They are;

1. ELISA test: People develop antibodies to HIV within 2-8 weeks of infection. ELISA test, which stands for enzyme-linked immunosorbent assay, is used to detect HIV infection using antibodies. Test is done with the use of blood.

2. Western blot test: If an ELISA test is positive, the Western blot test or indirect fluorescent antibody (IFA)  is usually administered to confirm the diagnosis.

3. Antibody/antigen combination tests: They check for HIV antigen, a protein called p24 that's part of the virus and shows up 2-4 weeks after infection. They also check for HIV antibodies. A rapid antibody/antigen test can give results in 20 minutes with 99 percent accuracy. Blood is the fluid used.

Virologic testing is recommended for children between four and six weeks of age. Using serological antibody tests may come out positive due to persistent mother antibodies in the child up to 15-18 months.

4. Viral load count: Three technologies measure HIV viral load in the blood: reverse transcription polymerase chain reaction (RT-PCR), branched DNA (bDNA) and nucleic acid sequence-based amplification assay (NASBA or NAATs). Viral load between 45 to 70 can be detected. NAATs are very accurate and expensive. Gives result after about 10-33 days of exposure to the virus. Also it uses blood.

5. Drug resistant assessment, phenotype testing and genotypic resistance testing is intended to investigate if the virus is resistant to a particular drug and the best treatment approach.

6. CD4 cell count: blood test to measure the quantity of remaining CD4 as a function of immune system or advance stage of HIV infection. In Nigeria, it is used to detect when to begin treatment. It is use to check if treatment is working. Normal CD4 count is 500-1600 mm³.

The WHO has approved the use of oraquick rapid  diagnostic home tests. This test detects the presence of antibodies to HIV. It is designed to be used at home. It uses saliva. Urine is not as accurate as blood and saliva.

However, laboratory tests are the standard for diagnosing HIV. The home test is just for quick diagnosis which must be confirmed in the laboratory.

Because of the stigma attached to HIV, people are scared to go for a test. And when they do, they suffer withdrawal syndrome before the result is out and even after. To prevent this, the client is counselled on HIV and what to expect after the result is out.

The WHO recommend the following guidelines;

1. Informed consent

2. Confidentiality

3. Counselling

4. Correct test results

5. Connect or link to a care, treatment and other services center.

The above can be achieved in the hospital. But that is not the case with home testing kits. So therefore, it is the duty of the personnel handling these products to do their best in counselling the cloner not only on how to use it, but also what to do before and after testing.

Pharmacotherapy/Treatment Of HIV

There is no drug for cure or vaccine. Only a few cases have been cured using bone marrow transplant. Available drugs are for management of the infection. Management entails reducing viral load and increasing CD4 cell counts.

It is recommended that treatment should start immediately when the person is diagnosed. And treatment is for life. Because of the cost of drugs, many people cannot afford the drugs especially in low income countries.

To help developing countries and their citizens, many western countries and rich individuals made provisions for drugs to be made available to low income countries and its citizens. But because the number of new infections is increasing, the financial burden is growing at an alarming rate. Most of these countries and individuals are pulling out. This is pushing poor countries to have a rethink on their strategies.

Most developing countries that heavily rely on foreign donors to sponsor their HIV programmes can no longer afford to start treatment immediately when HIV is diagnosed. They wait until the viral load is high or CD4 cell count falls below 1000 mm³ before initiating treatment. The consequence is the short life expectancy.

The life expectancy in 1990 was 19 years. That is a person who contracts HIV at the age of 29 will most likely die at the age of 39 years. However, due to better drugs and knowledge of the virus, life expectancy has jump to 53 years in 2020. That is a person who is 20 years old with HIV will live up to 73 years. But this life expectancy calculation is based on an infected person living a healthy lifestyle.

There are so many drugs available to treat HIV today. So many are no longer available due to reduced efficacy, some side effects and availability of better alternatives i.e. amprenavir replaced by fosamprenavir or delavirdine and zalcitabine (ddC) out of production because of limited use. Also, TAF is a more targeted form of tenofovir that has demonstrated high antiviral efficacy at a dose that is 10 times lower than that of tenofovir DF, as well as an improved renal and bone safety profile. But Tenofovir DF is still in circulation that may soon go into extinction.

Medication Summary

Suppressing viral load and increasing CD4 cell count is the target of therapy. The major way to achieve that is the use of ARV. Highly active antiretroviral therapy (HAART) is a treatment regimen typically composed of a combination of three or more antiretroviral drugs. HAART may also be called antiretroviral therapy (ART) or combination antiretroviral therapy (cART). Guidelines change as more knowledge about the virus and new drugs make their way into the scene.

Therapy should involve combinations of drugs recommended by current guidelines. Recommendations are specific for various patient groups (e.g. treatment naïve, treatment experienced, coinfection with hepatitis.

Combination therapy reduces the possibility of resistance and better slows progression to AIDS by reducing viral load.

Many of the antiretroviral drugs that have been approved for HIV-infected adults and adolescents are gaining FDA approval for use in younger children.

Antiretroviral Drug Classes and Agents

There are more than 25 antiretroviral drugs approved to treat HIV. They are group into six classes;

a. Nucleoside reverse transcriptase inhibitors (NRTIs):

1. Abacavir (Ziagen, ABC)

2. Didanosine (Videx, Videx EC, ddI)

3. Emtricitabine (Emtriva, FTC)

4. Lamivudine (Epivir, 3TC)

5. Stavudine (Zerit, Zerit XR, d4T)

6. Tenofovir DF (Viread, TDF)

7. Tenofovir AF (TAF)

8. Zalcitabine (HIVid, ddC)*

9. Zidovudine (Retrovir, ZDV, AZT)

b. Protease inhibitors (PIs):

1. Amprenavir (Agenerase, AVP)*

2. Atazanavir (Reyataz , ATV)

3. Darunavir (Prezista, DRV)

4. Fosamprenavir (Lexiva, f-APV)

5. Indinavir (Crixivan, IDV)

6. Lopinavir and ritonavir (Kaletra, LPV/r)

7. Nelfinavir (Viracept, NFV)

8. Ritonavir (Norvir, RTV)

9. Saquinavir (Invirase [hard gel] capsule, SQV)

10. Tipranavir (Aptivus, TPV)

c. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

1. Delavirdine (Rescriptor, DLV)

2. Efavirenz (Sustiva, EFV)

3. Etravirine (Intelence, ETR)

4. Nevirapine (Viramune, NVP)

5. Rilpivirine (Edurant)

6. Doravirine (Pifeltro, DOR)

d. Fusion inhibitors:

1. Enfuvirtide (Fuzeon, T-20)

2. Cellular chemokine receptor (CCR5) antagonists

3. Maraviroc (Selzentry, MVC)

e. Integrase inhibitors

1. Raltegravir (Isentress, RAL)

2. Dolutegravir (Tivicay, DTG)

3. Elvitegravir (Vitekta, EVG)

f. Entry inhibitors:

1. CD4 post-attachment inhibitors e.g. Ibalizumab (IBA)

2. gp120 Attachment inhibitors e.g. Fostemsavir (FTR) (No longer available on market).

Treatment includes the use of three ARV medications from at least two classes of drugs. Ritonavir, a PI that may be used in its own right, boosts blood levels of other PIs. This permits a reduced dosage of the coadministered drug. Various products have been formulated to include PIs combined with ritonavir. There are several combination therapies for different drugs and doses. Those available in each country are determined by research on efficacy and availability.

Antiretroviral Combination Products

First Line Therapy

1. First recommendation: 1 NNRTI+2 NRTI (zidovudine or Tenofovir and lamivudine or emtricitabine)

2. Second recommendation: DTG/3TC/TDF

3. Third recommendation: TDF/3TC/efavirenz as alternative

Note: Protease inhibitors added if the above losses efficacy. They are not used alone.

High-genetic-barrier INSTI or protease inhibitors pharmacologically boosted with cobicistat or ritonavir (PI/b) are recommended as initial therapy for primary HIV infection if resistance testing is unavailable.

Ritonavir- or cobicistat-boosted darunavir (DRV/b) plus rilpivirine (RPV) has been included as a dual-therapy option.

Monotherapy with PI/b is not recommended.

Drug Content per Tablet/Capsule

Numerous antiretroviral combination products are available on the market to assist patients with compliance and decrease the daily number of tablets and capsules required.

This is a complete once-daily regimen in adults who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable ART regimen for ≥6 months with no history of treatment failure and no known substitutions associated with resistance

1. Darunavir 800 mg + Cobicistat 150 mg + Emtricitabine 200 mg + Tenofovir AF 10 mg taken 1 tab PO qd with food

2. Bictegravir 50 mg + Emtricitabine 200 mg + Tenofovir AF 25 mg taken 1 tab PO qd

3. Efavirenz 400 mg + Lamivudine 300 mg + Tenofovir DF 300 mg taken 1 tab PO qHS on an empty stomach

4. Efavirenz 600 mg + Lamivudine 300 mg + Tenofovir DF 300 mg taken 1 tab PO qHS on an empty stomach

5. Dolutegravir 50 mg + Rilpivirine 25 mg taken 1 tab PO qd with a meal

This a complete once-daily regimen in treatment-naïve adults with no known substitutions associated with resistance to dolutegravir or lamivudine

1. Dolutegravir 50 mg + Lamivudine 300 mg taken 1 tab PO qd with or without food

2. Elvitegravir 150 mg + Cobicistat 150 mg + Emtricitabine 200 mg + Tenofovir AF 10 mg taken 1 tab PO qd

3. Elvitegravir 150 mg + Cobicistat 150 mg + Emtricitabine 200 mg + Tenofovir DF 300 mg taken 1 tab PO qd

4. Abacavir 600 mg + Lamivudine 300 mg taken 1 tab PO qd

5. Abacavir 600 mg + Dolutegravir 50 mg + Lamivudine 300 mg taken 1 tab PO qd

6. Abacavir 300 mg + Lamivudine 150 mg + Zidovudine 300 mg taken 1 tab PO bid

7. Efavirenz 600 mg + Emtricitabine 200 mg + Tenofovir DF 300 mg taken 1 tab PO qd on empty stomach.

Note: May be used alone as a complete regimen or in combination with other ARTs

1. Emtricitabine 200 mg + Rilpivirine 25 mg + Tenofovir DF 300 mg taken 1 tab PO qd with a meal

2. Emtricitabine 200 mg + Rilpivirine 25 mg + Tenofovir AF 25 mg taken 1 tab PO qd with a meal

3. Emtricitabine 200 mg + Tenofovir DF 300 mg taken 1 tab PO qd

Dosage adjustment is needed in CrCl of 30-49 mL/min: 1 tab PO q48h and when the CrCl < 30 mL/min, do not administer

4. Emtricitabine 200 mg + Tenofovir AF 300 mg taken 1 tab PO qd

Dosage adjustment is needed when CrCl < 30 mL/min, do not administer

5. Lamivudine 150 mg + Zidovudine 300 mg taken 1 tab PO bid

6. Lamivudine 300 mg + Tenofovir DF 300 mg taken 1 tab PO qd

7. Doravirine 100 mg + Lamivudine 300 mg + Tenofovir DF 300 mg taken 1 tab PO qd with or without food

Antiretroviral Therapy And Opportunistic Infection

Initiation of ART in patients with tuberculosis (TB) and HIV coinfection who have a CD4 cell count of more than 50/µL may be deferred up to 8 weeks after TB treatment has been started.

Combined antiretroviral therapy (cART) containing integrase strand transfer inhibitor (INSTI) has been shown to be superior to boosted protease inhibitor (PI) in chronic HIV-infected patients. INSTI-based regimens are as follows:

1. Bictegravir/tenofovir + alafenamide/emtricitabine (single-tablet regimen)

2. Dolutegravir/abacavir/lamivudine (single-tablet regimen) - Only for patient without chronic hepatitis B virus (HBV) coinfection (In women of childbearing age, discuss the risks and benefits of prescribing dolutegravir around the time of conception, including the low risk of neural tube defects [NTDs] and the relative lack of information regarding the safety of using other commonly prescribed antiretrovirals [ARVs]).

3. Dolutegravir + (emtricitabine or lamivudine) + (tenofovir alafenamide or tenofovir disoproxil fumarate)

4. Raltegravir + (emtricitabine or lamivudine) + (tenofovir alafenamide or tenofovir disoproxil fumarate)

5. Dolutegravir + lamivudine - Except in individuals with HIV RNA of more than 500,000 copies/mL, persons with HBV coinfection, or patients in whom ART is to be started before the results of HIV genotypic resistance for reverse transcriptase or HBV testing are available

6. The PI/r–based regimen is darunavir/ritonavir+(tenofovir alafenamide or tenofovir disoproxil fumarate) + (emtricitabine or lamivudine)

Lifestyle

Drugs are to manage the virus. However, a healthy lifestyle will help the drug work better. Healthy eating, exercise and avoiding alcohol, smoking and other risky lifestyles makes HIV infections worse. Vitamin A, zinc and iron should be avoided because they can produce adverse effects.

Vaccination against some opportunistic infections does help. Isoniazid preventive therapy (IPT) is to prevent TB. Trimethoprim/sulfamethoxazole is used as a prophylaxis against toxoplasmosis and used between four and six weeks.

Read Also: How to prevent HIV infection

Prevention

1. For prevention against sex related transmission, the ABC rule apply. They are;

a. Abstain: unmarried people are encourage to desist from sex until they are married.

b. Be faithful: married people are encouraged to stay faithful to their sexual HIV free sexual partners. The advice also goes to singles who are into relationships.

c. Condom: condom does not prevent all STI but it does prevent HIV infections in 85 percent of cases. It is only efficient when worn properly. Some claim that male condoms are more effective than female condoms.

2. It has been shown that male circumcision reduce the rate of infection

3. Mother to child transmission can be prevented by treating the mother during pregnancy and breastfeeding using ARV.

4. PEP and PrEP:

PEP: There are cases in which some people are exposed to HIV. For example, a nurse or medical doctor giving an infected person injection and mistakenly pricking the skin with the same needle will need postexposure prophylaxis (PEP).

PEP drug regimens are given at least 72 hours after exposure. The client is counselled, tested and given PEP for 28 days. The following regimen is recommended by center for disease control (CDC):

Preferred option 1: Dolutegravir + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)

Preferred option 2: Raltegravir + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)

Alternative: tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) + darunavir + ritonavir daily.

Raltegravir (RAL) 400 mg twice daily or dolutegravir (DTG) 50 mg daily in combination with tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine (FTC) 200 mg daily, and bictegravir (BIC) have been added as potential drugs for postexposure prophylaxis (PEP).

PrEP: When somebody intends to have dealings with an infected person such as a medical doctor performing an operation on a HIV infected patient, HIV pre-exposure prophylaxis (PrEP) regimens are needed. It helps prevent infection. It is taken two drugs 24 hours before exposure. A second single dose is taken 24 hours after the first 2 drug. The last single pill is taken by 48 hours after the first doses.

Preferred PrEP drug regimen: tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)

Alternative: tenofovir alafenamide (TAF) 25 mg + emtricitabine (FTC) 200 mg. Recommended dosing is 1 tablet PO daily.

TAF/FTC is now included as an alternative for pre-exposure prophylaxis (PrEP) in men who have sex with men (MSM) and transgender women.

Side Effects Of ARV

Adherence is a major problem with ARV. This is because the drugs must be taken everyday at a particular time. To make matters worse, most of these drugs have side effects that are worth noting. They are diarrhea, difficulty sleeping, dry mouth, nausea and vomiting, headache, dizziness, fatigue, rash and body pain.