The Joint United Nations Programme on HIV/AIDS (UNAIDS) 95:95:95 goal is to have 95% of people living with human immunodeficiency virus (HIV) know their HIV status, 95% of people who know their status in treatment and 95% of people on HIV therapies have suppressed viral loads by 2030, thereby ending the global epidemic. These targets are based on the fact that individuals living with HIV who are in treatment and maintain an undetectable viral load have quantities of HIV in their bodily fluids that are untransmittable to others. This is known as the U=U concept—undetectable=untransmittable.

However, the large number of HIV positive individuals who go undiagnosed or untreated, viral resistance to antiretroviral drugs and breakthrough infections in those taking pre-exposure prophylaxis (PrEP) are complicating the path to ending the epidemic.

Undiagnosed, Untreated Individuals Contribute Significantly to New Infections

HIV-infected individuals typically experience flu-like symptoms within 2-4 weeks of exposure. During this acute phase of infection, the virus replicates rapidly, and HIV RNA and HIV p24 antigen levels rise. After the acute phase of infection, the rate of HIV replication slows. More serious symptoms of HIV infection, such as opportunistic infections like Karposi’s sarcoma, can take years to manifest. Without treatment, HIV infections eventually advance to acquired immunodeficiency syndrome (AIDS).

The U.S. Centers for Disease Control and Prevention (CDC) estimates that roughly 1.2 million people in the U.S. have HIV and, of those individuals, 153,500 (~13%) are not aware that they are living with HIV and urgently need testing. Notably, approximately 80% of new HIV infections originate from HIV-positive individuals who do not know their status or are not receiving HIV therapies. Moreover, for every 100 individuals diagnosed with HIV in the U.S. in 2021, only 75% received some HIV care and 66% were virally suppressed (<200 copies of HIV per milliliter of blood). These numbers fall far short of the 95:95:95 goal, perpetuating the cycle of transmission.

What's the Impact of Viral Drug Resistance?

Antiretroviral treatment (ART) and the initiation of single tablet regimens drastically reduced HIV morbidity, mortality and prevalence. Antiretroviral HIV drugs encompass 7 drug classes, grouped by how the drug(s) dysregulate the viral life cycle. These classes include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 antagonists, post-attachment inhibitors and integrase strand transfer inhibitors (INSTIs).

First line treatment regimens typically consist of 2 nucleoside reverse transcriptase inhibitors (NRTIs) prescribed in combination with 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Regular viral load monitoring is imperative to ensure that treatments are working effectively to suppress the virus, and that the patient is not able to transmit the virus to sexual partners.

If treatments are missed or inconsistently taken, viral replication resumes. Each round of replication is an opportunity for mutations in the viral genome, which could potentially confer drug resistance. Random mutations that lead to ART resistance render the patient’s treatment regimen ineffective and create an environment where the mutant quasi-species thrives over wild-type quasi-species when treatment is resumed. For example, resistance in individuals who re-initiated efavirenz and nevirapine (both NNRTIs) after stopping treatment was 21% higher compared to first-time users. Drug-resistant strains are then transmissible to subsequent sexual partners.

The impact of a mutation on a patient's treatment options varies depending on the specific mutation, and performing drug resistance testing can aid in selecting an alternative treatment regimen. Certain classes of drugs are more vulnerable to debilitating mutations than others. For example, some single base mutations can confer high-level drug resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTI/NtRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) drug classes. Conversely, multiple simultaneous mutations need to occur to confer resistance to protease inhibitors (PI).

From 2014-2018, HIV drug resistance to NNRTIs exceeded 10% in the majority of countries who report data to the World Health Organization (WHO), with the rate of HIV drug resistance in women almost double that seen in men in the same areas. (Because of WHO recommendations for reducing mother-to-child transmission, many women living with HIV were prescribed antiretrovirals throughout pregnancy and then terminated treatment post delivery. In 2015, the WHO changed the guidance and recommended that expectant and breast-feeding HIV positive mothers remain on antiretrovirals for life). The increasing prevalence of drug resistant strains complicates the path to achieving viral suppression in 95% of people living with HIV.

How Do PrEP Breakthrough Infections Occur?

Pre-exposure prophylaxis (PrEP) is a highly effective intervention that helps prevent HIV acquisition in HIV-negative individuals who are at high risk of becoming infected. PrEP, in conjunction with safer sex counseling and safer injection practices, is a cornerstone in reducing HIV incidence. PrEP is a single daily pill containing 2 NRTI drugs, tenofovir and emtricitabine, which, when taken consistently, prevents HIV from establishing an infection.

Although PrEP is highly effective for preventing HIV transmission, some concerning breakthrough infections have occurred. In 1 example, it was difficult to discern, due to lack of monitoring, if the breakthrough infection occurred because the patient was exposed to tenofovir- and emtricitabine-resistant HIV, or if the patient acquired HIV, and due to subtherapeutic drug levels from incomplete PrEP adherence, resistance to tenofovir and emtricitabine emerged. This highlights the necessity of strict adherence to the PrEP regimens to prevent widespread HIV resistance. Although concerning, the likelihood of breakthrough infections occurring in individuals consistently taking PrEP is rare.

Finally, there are concerns that the potential benefits of PrEP could be offset as people feel there is an added layer of protection, and thus are more willing to engage in high-risk behaviors. The increasing use of PrEP is associated with decreased condom usage and also coincides with an increase in other sexually transmitted infections (STIs). PrEP needs to be accompanied by education from healthcare providers explaining why vulnerable populations need to continue to participate in safe sex practices. Furthermore, public health advocates need to continue to promote condom usage in all at-risk populations.

We need improved global HIV screening and HIV drug resistance screening programs if the UNAIDS 95:95:95 goal is going to be met. Further research and innovation are essential to ensure that new, efficacious therapies continue to be available to patients. Although the HIV landscape has dramatically improved over recent decades, much work is still needed if global targets to end the HIV/AIDS epidemic are to be met.