The silent signal that could determine the future of HIV treatment.
For the nearly 1.2 million people living with HIV in the United States, antiretroviral therapy (ART) has been a life-saving revolution, allowing them to suppress the virus to undetectable levels—a state known as "undetectable equals untransmittable" or U=U. Yet for a significant number, including many women, HIV persists in a subtle, gray zone known as low-level viremia (LLV)—a consistent but low presence of virus in the blood that falls below the traditional threshold for treatment failure.
This persistent low-level detection of the virus presents a complex clinical puzzle. Is it a harmless blip or a warning sign of future treatment problems? Emerging research reveals that the implications of LLV may be particularly consequential for women, potentially influencing both treatment outcomes and long-term health in ways we are just beginning to understand.
When we talk about an "undetectable" viral load, we mean that the amount of HIV in a person's blood is below the cutoff point that standard tests can reliably measure—usually below 50 copies/mL. Virological failure, on the other hand, is typically defined as a viral load consistently above 200 copies/mL5 .
Low-level viremia occupies the middle ground between these two states. While definitions vary slightly between guidelines, LLV is generally defined as persistently detectable HIV RNA levels between 50-200 copies/mL1 5 . It's crucial to distinguish this from a "viral blip"—a temporary, isolated detectable reading that quickly returns to undetectable levels.
| Organization | Low-Level Viremia (LLV) | Viral Blip | Virological Failure |
|---|---|---|---|
| U.S. DHHS (2021) | Confirmed detectable HIV RNA <200 copies/mL | Isolated detectable reading followed by return to suppression | Inability to maintain HIV RNA <200 copies/mL |
| International Antiviral Society (2020) | 50-200 copies/mL | Isolated increase to <1,000 copies/mL returning to undetectable | Confirmed HIV RNA >200 copies/mL |
| World Health Organization | 50-1,000 copies/mL | Intermittent low-level viraemia (50-1,000 copies/mL) | VL >1,000 copies/mL based on two consecutive measurements |
For years, the clinical significance of LLV remained debated. Now, a growing body of evidence paints a clearer—and concerning—picture of its potential consequences.
Ongoing replication at low levels allows HIV to accumulate drug resistance mutations1 .
To understand how we know what we know about LLV, let's examine one of the most comprehensive recent studies on this phenomenon.
Participants
Centers Across Spain
Average Follow-up
Projected Outcomes
Professor Enrique Bernal and colleagues analyzed data from the Spanish HIV/AIDS research network (CoRIS), which included ART-naive adults recruited from 47 centers across Spain7 . Their approach was meticulous:
The study included people who started HIV treatment for the first time, achieved viral suppression below 50 copies/mL, and had sufficient follow-up data.
They defined LLV as having two consecutive viral load measurements between 50-200 copies/mL, carefully excluding cases where viral load previously exceeded or later rose above 200 copies/mL.
Participants were classified into two groups: the "No-LLV" group (maintaining viral load ≤50 copies/mL or having only single detectable measurements) and the "LLV" group (meeting the strict definition of persistent low-level detection).
The study's findings provided crucial insights into the real-world impact of LLV:
The clear increased risk of treatment failure in the LLV group (12.3% vs. 4.7%) underscores that even low-level detectable virus represents an unstable situation that demands attention1 .
The researchers found that integrase inhibitor-based regimens were protective against treatment failure in the context of LLV, while protease inhibitor-based regimens increased risk1 .
| Outcome Measure | Undetectable Group | LLV Group |
|---|---|---|
| Probability of Virological Failure | 9% | 21% |
| Probability of AIDS Conditions | 0.4% | 1.06% |
| Probability of Non-AIDS Conditions | 14.3% | 16.4% |
Note: Differences in clinical outcomes (AIDS and non-AIDS conditions) were not statistically significant1
While research specifically focusing on women with LLV remains limited, emerging evidence suggests that sex and gender differences may play an important role in the LLV landscape.
A 2025 review of the evolving clinical landscape of LLV noted that the effects of low-level viremia "may be more pronounced among women"4 . This means that the same level of low-level viremia might have different implications for women compared to men, though the exact reasons require further investigation.
Several factors may contribute to this potential heightened impact:
Women may metabolize antiretroviral drugs differently, potentially affecting drug concentrations and efficacy.
There are known differences in immune system functioning between sexes that might influence how the body controls HIV at low levels.
Hormonal fluctuations across the menstrual cycle, during pregnancy, or with menopause might interact with HIV replication and treatment effectiveness.
Women, particularly women of color, often face greater barriers to consistent healthcare access and medication adherence due to caregiving responsibilities, transportation challenges, or financial constraints2 .
| Risk Factor | Impact on LLV Risk | Notes |
|---|---|---|
| Low CD4 Nadir (<200 cells/μL) | Increased | Suggests greater initial immune damage2 6 |
| High Baseline Viral Load (>100,000 copies/mL) | Increased | Indicates more established infection before treatment |
| Older Age at ART Initiation | Increased | Particularly age ≥50 years6 |
| Protease Inhibitor-Based Regimens | Increased | Compared to integrase inhibitors1 6 |
| Poor ART Adherence | Increased | Though not the sole cause of LLV2 |
| Homosexual Transmission | Decreased | Possibly reflecting demographic or healthcare access factors |
Low-level viremia represents a nuanced challenge in the modern era of HIV treatment—one that may hold particular significance for women living with HIV. While not an emergency, LLV is far from benign; it serves as an important warning sign that demands attention, not alarm.
The key takeaway for women navigating life with HIV today is that maintaining open communication with healthcare providers, adhering consistently to prescribed regimens, and ensuring regular viral load monitoring remain the cornerstones of effective long-term management. As research continues to unravel the complexities of this viral "gray zone," the prospects for ever-more-effective strategies to achieve and maintain complete viral suppression grow brighter.