This Week in HIV Research: The Frustrating Relativity of Efficacy
As information—and misinformation—flies unfiltered across the internet regarding the viability of certain drug combinations in the treatment of COVID-19, we’re reminded of the challenges of reliably proving efficacy of interventions outside of large, randomized, controlled clinical trials.
With COVID-19, the pressure to yield encouraging results is intense because of the urgency of the pandemic, making efficacy studies even more fraught—and making it hard to properly message the results of those studies for the public. The HIV pandemic has a much longer history, of course (not to mention a much longer incubation period, among many other differences that make most comparisons between the two viruses moot), but three decades into our research on HIV, we still see how difficult it can sometimes be to gauge the efficacy of our interventions.
In recent days, we’ve seen these two viral worlds collide, as they have in the first study we highlight this week. We’ve also seen examples of the debate over efficacy in other areas of HIV research, a few of which we’ll summarize below.
To wit, this week we’ll explore:
- The efficacy of the HIV protease inhibitor lopinavir/ritonavir (Kaletra) as COVID-19 treatment.
- The extent to which pre-exposure prophylaxis (PrEP) scale-up has a population-level impact on HIV diagnoses.
- The long-term cost-effectiveness of a wide range of HIV interventions.
- Disparities in virologic suppression—i.e., the real-world efficacy of antiretroviral therapy—among young people living with HIV.
We’ll do our best to effectively recap each of these noteworthy published findings. To beat HIV, you have to follow the science!
Lopinavir/Ritonavir Appears Ineffective Against COVID-19
A “quick and dirty” study among 199 severely ill patients hospitalized for COVID-19 in Wuhan, China, found no difference in time to clinical improvement or mortality between those randomized to lopinavir/ritonavir for 14 days or standard of care only.
Because this was an emergency trial, no placebos were prepared, and no data on various confounders were available. The study was published in New England Journal of Medicine.
In the intent-to-treat analysis, median time to clinical improvement was 16 days in both arms, and 28-day mortality was 19% among people receiving the antiretroviral vs. 25% among those receiving standard-of-care treatment. In a modified intent-to-treat analysis, those on the study drug improved one day faster than those in the control arm (15 vs. 16 days). There was no difference in the time to clinical deterioration.
People living with HIV (PLWH) were excluded from this trial because of concerns that they might develop resistance against the lopinavir/ritonavir if they took it without the other antiretrovirals that would comprise a typical treatment regimen.
No data on COVID-19 variants that might be less susceptible to lopinavir were available. It is thus unclear whether a combination of lopinavir and other antivirals might be more effective. In addition, because of the study drug’s side effects, testing it with a higher dose or longer administration period are not under consideration, the authors stated.
Researchers Debate Population-Level Impact of PrEP
A dueling study-and-commentary combination in a recent issue of Clinical Infectious Diseases raises conflict-of-interest concerns amidst a conversation regarding the results of efforts to scale up PrEP access in the U.S.
The study compared state-level data on annual HIV diagnoses and PrEP prescriptions from a single pharmacy database over a four-year period (2012-2016). It concluded that the estimated annual percentage change in diagnosis rates dropped by 4% in the 10 states with the greatest increase in PrEP coverage.
The authors conceded that this is an association, not a causal relationship. Nonetheless, they called for scaling up PrEP to everyone at high risk for seroconversion, contending that the data indicated a population-level benefit of doing so.
While the accompanying commentary agreed with the need for further scale-up of PrEP availability and lamented its slow uptake, it called into question the extent to which the study findings should be used to link greater PrEP access to a reduction in HIV diagnoses, and to make policy decisions based on that suggestion.
The comment authors—Julia Marcus, Ph.D., M.P.H., of Harvard Medical School; A. David Paltiel, Ph.D., of Yale School of Public Health; and Rochelle Walensky, M.D., M.P.H., of Massachusetts General Hospital—questioned the choice of data points on which the study chose to focus, noting that a PrEP prescription does not mean the patient is actually taking the medication, and that HIV diagnosis rates are not incidence rates. They also noted that the prescription data excluded large pharmacy networks, such as Kaiser Permanente.
Marcus et al. added that greater PrEP rollout may also increase the frequency of HIV testing or linkage to care, which could affect diagnosis rates independent of the prevention medication. In the era of U=U, viral suppression rates could further influence the effect of biomedical prevention: With everyone virally suppressed, PrEP would make little difference in seroconversion rates.
Some unavoidable context to the tension between the study and the commentary lies within their respective conflict of interest statements: Two of the 10 study authors are employed by and are shareholders of Gilead Sciences, the maker of both PrEP medications currently on the U.S. market. Meanwhile, one of the three comment authors disclosed a consulting relationship with Kaiser Permanente and the receipt of a Gilead research grant.
Ultimately, the commentary authors concluded their critique with a call for further population-level studies on PrEP’s impact. “In the meantime, while PrEP remains an essential component of our HIV prevention strategy, the jury is still out on its population-level impact,” they wrote.
More HIV Testing Cost-Effective Everywhere, Other Prevention Measures Vary
Among a menu of different options for localized HIV interventions in major U.S. cities, the most widely cost-effective over the long term are those that involve increased HIV testing efforts, a study published in AIDS showed. PrEP scale-up targeted specifically at men who have sex with men (MSM) was also found to be cost-effective in some cities, but not all.
A team of Canadian and U.S. researchers modeled the cost-effectiveness of 16 evidence-based strategies recommended by the Centers for Disease Control and Prevention in six U.S. cities with different microepidemics: Atlanta, Baltimore, Los Angeles, Miami, New York City, and Seattle. The strategies included four HIV prevention programs, five HIV testing programs, five HIV treatment engagement programs, and two HIV treatment re-engagement programs. The researchers calculcated incremental cost-effectiveness ratios over 20 years for scaling up each intervention from its current level.
Higher HIV testing levels were cost-effective or cost-saving in all cities studied. After diagnosis, getting more people onto treatment earlier showed the greatest financial benefit compared to other methods for improving care engagement.
Interventions such as scaling up syringe services or MSM-targeted PrEP only added value if the existing level of these services was not already high in a given locality. While expanding medication for opioid use disorder did not greatly impact HIV incidence, it was often still cost-effective because it lowers mortality from hepatitis C and other causes.
“No single intervention was projected to reduce HIV incidence by more than 10.1% in any city,” study authors noted. They recommended a combination of implementation strategies that is tailored to each local context, as well as addressing barriers to HIV care access to meet the “Ending the Epidemic” targets.
Significant Disparities in HIV Suppression Seen Among Young Americans
Sustained viral suppression rates are especially low among young people in the U.S., and even more so among young Black MSM, researchers reported in Journal of Acquired Immune Deficiency Syndromes. Improving these rates is not only important for individual health, but also for preventing HIV transmissions.
In 2016, 23% of the U.S. population was 13 to 29 years old, but 42% of new HIV diagnoses were in that age group, the study found. Twenty-eight percent of 90,812 young PLWH had no viral load test during that year, while 42% had a viral load < 200 copies/mL for each of their tests during that year—the study’s definition of sustained viral suppression.
Overall, MSM had the highest rate of viral suppression, while people who inject drugs and those who acquired HIV perinatally had the lowest rates.
African Americans accounted for 54% of MSM diagnosed with HIV, but only 38% of MSM with sustained viral suppression.
To end the HIV epidemic, we must address these disparities, study authors wrote. They suggested two possible interventions:
- A centralized service model with adolescent care providers.
- The use of mobile phone technology and social media to reach young people.
Greater awareness of “undetectable equals uninfectious” messaging in that age group may motivate people to get tested, combat stigma, and offer an opportunity for discussing HIV prevention, they added.