Antiretroviral therapy: the breakthrough HIV treatment explained

In 1987, AZT (zidovudine) was fast-tracked through the United States Food and Drug Administration’s (FDA) approval process. In so doing, it became the first medication to be used to treat human immunodeficiency virus (HIV). AZT had previously been developed in the 1960s as a potential anti-cancer drug, but when it failed to be effective, it was mostly forgotten about. Then, in the heat of the acquired immunodeficiency syndrome (AIDS) epidemic of the 1980s, it resurfaced while researchers attempted to find anything that might be effective against HIV. After a phase II trial of AZT in 1986 was stopped for ethical reasons (Broder, 2010). There were 1/145 deaths in the treatment group vs. 19/137 in the placebo group. As such, it was not ethical to withhold the drug from individuals with AIDS and AZT was allowed to move forward to be used as treatment. The results of that trial and the actual efficacy of AZT have since been called into question—although it is still used as part of some people’s HIV treatment today. At the time, however, the drug meant more than just treatment—it was a symbol of hope.

Medicine has come a long way in 30 years. Today, there are dozens of medications that can be used to treat HIV. These drugs are broadly divided into seven classes, each of which acts on a different part of the HIV life cycle. When these drugs are used in combination to fight HIV, it is called antiretroviral therapy (ART). The terms combination antiretroviral therapy (cART) and highly active antiretroviral therapy (HAART) are sometimes used as well.

Treatment of HIV is critically important. Without it, HIV is a fatal diagnosis. With it, the life expectancy of HIV-positive individuals is approaching that of people who do not have HIV. And while there still is no cure for HIV, proper treatment of HIV can make an individual’s viral load undetectable. What this means is that, with proper medications and time, the amount of virus in a person’s blood can become so low that laboratory tests are no longer able to detect it. When somebody has undetectable HIV, they are unable to pass the virus to anybody else through sexual contact. The chances of transmitting HIV through pregnancy, labor, delivery, and breastfeeding are also significantly reduced. Treatment of HIV is therefore important because it can lead to a better quality of life for an HIV-positive individual, and it can help prevent the spread of the virus.

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HIV is a virus that infects the human immune system. It is most commonly found in sub-Saharan Africa, but it began appearing in large numbers in the United States in the 1980s, particularly in men who have sex with men (MSM). HIV can infect everyone, including women and infants.

HIV infection is typically spread through sexual contact (anal sex, oral sex, and vaginal sex) as a sexually transmitted infection (STI). But it can also be passed from mother to child during pregnancy and breastfeeding or through contact with infected blood, like by sharing needles during intravenous drug use. Initial infection with HIV causes a flu-like illness that is usually characterized by fever and swollen lymph nodes, but it can also be asymptomatic. After the body fights off the initial infection, HIV enters a chronic phase called clinical latency, where levels of the virus in the body slowly rise again.

HIV infects the CD4+ T cells of the immune system. As levels of the virus rise, CD4 cell count decreases. When untreated, HIV can advance, bringing the CD4 count down over approximately ten years. When the CD4 count is <200 cells/mm3, an individual is diagnosed with AIDS. AIDS can also be diagnosed when an individual acquires an AIDS-defining illness, which is an infection or a complication that is a result of having a weakened immune system.

To understand the medications that are used to treat HIV, it is helpful first to understand how HIV infects a cell and the steps it goes through to reproduce:

1. Binding or attachment: HIV binds to the receptors of a CD4+ T cell. It does this by attaching to the CD4 receptor and to either the CCR5 or CXCR4 receptor.

2. Fusion: The membrane around HIV fuses to the membrane of the CD4 cell, allowing HIV to enter the cell.

3. Reverse transcription: An HIV enzyme called reverse transcriptase copies HIV’s genetic code from RNA into DNA.

4. Integration: An HIV enzyme called integrase incorporates the HIV DNA into the host cell’s DNA.

5. Replication: The host cell reads the HIV DNA, copying it into HIV RNA. The HIV RNA is then read, creating HIV proteins.

6. Assembly: HIV RNA and HIV proteins move towards the surface of the host cell and assemble into a noninfectious form of HIV.

7. Budding and maturation: The new HIV particles leave the host cell and continue to mature with the help of an HIV enzyme called protease. This makes the virus infectious again.

There are currently seven classes of drugs that can be used in the treatment of HIV. Each class targets a different part of the HIV life cycle.

The seven classes of HIV medicines are as follows (AIDSinfo-a, 2019):

• CCR5 antagonists: These medications block the CCR5 receptors on the cell surface. This prevents CCR5-dependent HIV from entering the cell. Currently, there is only one approved CCR5 antagonist medication called maraviroc.

• Post-attachment inhibitors: These medications block the entry of HIV into the cell after attachment. The only post-attachment inhibitor is called ibalizumab-uiyk, and it is used intravenously for those with multi-drug resistant virus.

• Fusion inhibitors: These medications bind to HIV, preventing fusion with CD4 cells. The only approved fusion inhibitor is enfuvirtide, which is an injection given twice daily.

• Nucleoside reverse transcriptase inhibitors (NRTIs): These medications block the action of reverse transcriptase, preventing the conversion of HIV RNA to HIV DNA. There are several medications in this class, and they are typically given in pairs. AZT is a type of NRTI.

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs): These medications block reverse transcriptase, preventing the conversion of HIV RNA to HIV DNA. There are several medications in this class.

• Integrase strand transfer inhibitors (INSTIs): These medications block the insertion of HIV DNA into the host cell’s DNA, which makes it so that copies of the virus cannot be made.

• Protease inhibitors (PIs): These medications block the action of protease, which turns noninfectious new HIV into infectious mature HIV. These medications should be given with another type of medication known as a pharmacokinetic enhancer, which can boost their efficacy.

Many of these medications have been made into combination pills that contain two or three different drugs in them. This can increase medication adherence among patients.

It is recommended that everybody begin treatment with HIV medication as soon as possible after diagnosis. This is true regardless of whether a person is experiencing the acute stage of the infection, the chronic stage of the infection, or AIDS. One study that looked into starting treatment immediately when CD4 >500 cells/mm3 versus postponing treatment until CD4 ≤350 cells/mm3 found that earlier treatment was associated with better outcomes (The Insight, 2015). Newer HIV drugs have better side effect profiles, which means they are easier to tolerate. The benefits of starting HIV treatment right away, therefore, outweigh the risks in most people.

The initial treatment of HIV typically includes two NRTIs plus one INSTI but could also be two NRTIs with either one NNRTI or one PI coupled with a booster. This is typically known as triple therapy because three medications are taken. In 2019, the FDA approved the first two-drug regimen that is intended to treat certain patients who are treatment-naïve (have never received ART) (FDA, 2019). This regimen consists of dolutegravir, an INSTI, and lamivudine, an NRTI.

Not everybody with HIV receives the same treatment. While there are many established treatment regimens, exactly which medications somebody begins with comes down to individual factors like tolerability, drug interactions, the presence of other medical conditions, cost, and convenience. Also, after being diagnosed with HIV, individuals should be evaluated for drug resistance. This is a way of testing the specific type of HIV that is infecting a person to determine whether the HIV has developed resistance to any medications. These results can guide initial treatment. It is also possible for drug resistance to develop over time, so somebody may need to change the medications they are taking if they stop working (even if they were effective at first). Drug resistance can occur if you go off of your medications or do not take them as prescribed because it allows the virus to replicate. Therefore, once you have started taking HIV medication, it is important to keep taking it unless directed by a healthcare provider. To learn more about what treatment regimen might be best for you, talk to your healthcare provider.

The treatment for AIDS is the same as the treatment for HIV and relies on picking the most effective medications from the list above as ART. If a patient remains compliant with treatment, they may never end up developing AIDS. However, some individuals do not receive treatment, are not adherent to treatment, or have treatment-resistant forms of HIV. When this is the case, CD4 levels continue to decline.

AIDS is characterized by having a CD4 cell count <200 cells/mm3. When the immune system is this weak, the body becomes prone to opportunistic infections. These are infections that cause disease in immunocompromised individuals but do not cause disease in individuals with healthy immune systems. To combat this, part of the treatment of AIDS involves vaccination and antibiotic prophylaxis. Certain antibiotics are typically offered at thresholds of CD4 count depending on risk factors and the results of blood tests. For example, for a CD4 cell count ≤200 cells/mm3, trimethoprim-sulfamethoxazole (brand name Bactrim) is given to prevent pneumocystis pneumonia (PCP). Other diseases that may require vaccination or prophylaxis include coccidioidomycosis, hepatitis A, hepatitis B, histoplasmosis, human papillomavirus (HPV), influenza, malaria, Mycobacterium avium complex (MAC), tuberculosis, strep, syphilis, talaromycosis, toxoplasmosis, and varicella-zoster virus (VZV) (AIDSinfo-b, 2019).

Despite all of these medications, there currently is no cure for HIV. However, proper treatment can result in an individual having an undetectable viral load within six months, which is a major step in the right direction for the health of the individual as well as for preventing the spread of the virus.

Now, if you have been paying attention to the news the past ten years or so, you may have seen headlines stating that two people have been cured of HIV. In 2008, it was announced that somebody dubbed the “Berlin Patient” was cured. And in 2019, a similar announcement was made about the “London Patient.” Both of these patients are individuals who had previously been diagnosed with HIV. However, their HIV is now said to be in “remission,” meaning that there is no sign of the virus in the body even though they are no longer taking HIV medication. Functionally, they are cured.

The road to “cure” in both of these patients was complex. Both of them received ART therapy, and both of them eventually developed a form of blood cancer - leukemia in the Berlin Patient and lymphoma in the London patient. They both underwent chemotherapy but eventually required a bone marrow transplant with stem cells to treat their cancer. In both cases, the selected donor had a mutation of the CCR5 receptor known as CCR5-delta 32. This mutation makes cells resistant to HIV. As a result, after the transplantation, both patients became resistant to HIV.

These two cases were certainly good news, but it is unlikely that this treatment method will ever be generalizable to the public. The patients both had very complicated treatment histories, and bone marrow transplants can be extremely risky and come with their own set of complications. Although this means there is still no cure available for everybody else, these two cases do at least provide some insight into how HIV may be treated in the future.

PrEP and PEP are methods of preventing HIV infection in people who are HIV-negative. PrEP stands for pre-exposure prophylaxis, and PEP stands for post-exposure prophylaxis.

PrEP is indicated for those who are at high risk of acquiring HIV. This includes HIV-negative individuals who have an HIV-positive partner, MSM, injection drug users, and others who engage in high-risk sexual behavior (such as condomless sex with people who do not know their HIV status). According to the Centers for Disease Control and Prevention (CDC), taking PrEP daily can reduce the chances of acquiring HIV through sexual contact by 99%. PrEP needs to be taken every day for at least twenty days to build up in the body and to be maximally effective. Currently, Truvada is the only medication available as PrEP. Truvada is a combination of two drugs that can also be used to treat HIV infection when used with a third drug. There are also clinical trials currently underway to evaluate whether other medications can be used as PrEP in addition to Truvada.

PEP is indicated for those who may have been recently exposed to HIV. PEP is intended for emergencies and should not be used regularly as a method of preventing HIV infection. Possible HIV exposures include needlestick injuries and unprotected sex with an individual of unknown HIV status. To be effective, PEP needs to be started as soon as possible and within 72 hours. It is then taken for four weeks. PEP is not 100% effective, but if started soon enough can decrease the chances of acquiring HIV.

Without treatment, the life expectancy of somebody who has been diagnosed with HIV depends on how much the disease has already progressed at the time of diagnosis. Some individuals may experience symptoms of acute (or initial) infection and may know that they were exposed to the virus. Therefore they may be diagnosed very close to when they acquired the disease. In others, HIV may have been asymptomatic, or symptoms may have gone unnoticed until the individual already has AIDS and has acquired an AIDS-related illness. Because of this wide range, the life expectancy for somebody who has been diagnosed with HIV and goes without treatment can be anywhere from a few months to upwards of ten years.

The story for somebody who is receiving treatment and stays compliant with medications and follow-up appointments is very different. While the life expectancy of an HIV-positive individual is still shorter, it is beginning to approach the life expectancy of an individual without HIV. The exact prognosis is different for each person and depends on many factors such as access to healthcare, response to treatment, and presence of other medical conditions.

The good news about all of this information is that treatment exists. For somebody who has access to healthcare, HIV can be well-managed with lifelong treatment and quality of life can be significantly improved.

However, HIV treatment is not readily available everywhere in the world. Limitations exist such as geography, access to the healthcare system, cost, or living in a country where HIV/AIDS is still heavily stigmatized. The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that in 2018, 79% of people with HIV knew their status, 78% of people who knew their status were accessing treatment, and 86% of people receiving treatment had viral suppression (UNAIDS, 2019). Clearly, there is room for improvement in terms of access to both testing and treatment. UNAIDS currently has a 90-90-90 goal, focused on increasing all three of these percents to 90% by the year 2020 (UNAIDS, 2017).

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How we reviewed this article

Every article on Health Guide goes through rigorous fact-checking by our team of medical reviewers. Our reviewers are trained medical professionals who ensure each article contains the most up-to-date information, and that medical details have been correctly interpreted by the writer.

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Current version

September 23, 2019

Written by

Mike Bohl, MD, MPH, ALM

Fact checked by

Tzvi Doron, DO

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About the medical reviewer

Tzvi Doron, DO

Dr. Tzvi Doron is Board Certified in Family Medicine by the American Board of Family Medicine.