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Expert Analysis: Insights for International Clinicians on New Data From CROI 2020

Josep M. Llibre, MD, PhD
Laura Waters, FRCP, MD
Released: April 21, 2020

Managing Coinfections in Persons With HIV

WHIP3TB: Efficacy of Weekly Isoniazid Plus Rifapentine for 12 Weeks as TB Prophylaxis in People With HIV

Josep M. Llibre, MD, PhD:
Our final discussion focuses on 2 reports addressing coinfection in PWH. The first report by Churchyard and colleagues[52] presented results on TB prophylaxis with 3HP from the open-label, 2-part, individually randomized, pragmatic phase III WHIP3TB trial.[53]

The trial enrolled 4207 PWH without evidence of active TB in South Africa, Ethiopia, and Mozambique. TB is highly endemic in these nations, where ≥ 20% of the population is estimated to have latent Mycobacterium tuberculosis infection. Consistent with this estimate, the study reported that 36.4% of participants at baseline had a positive QuantiFERON-TB Gold Plus test result, indicating likely infection with M tuberculosis.[52,54,55] Participants were randomized 9:9:2 to receive a single round of 3HP, 2 annual rounds of 3HP, or control treatment with 6H.[52]

The trial had 2 main primary objectives. The first objective covered Part A of the trial, which spanned the first year, and compared treatment completion in those receiving 3HP vs 6H. The second objective covered Part B and compared TB incidence between those randomized to 1 round of 3HP vs 2 rounds of 3HP.

WHIP3TB: Outcomes With Weekly Rifapentine Plus Isoniazid for 3 Months vs Daily Isoniazid for 6 Months

Josep M. Llibre, MD, PhD:
At 12 months, treatment completion was markedly higher in those who received 3HP vs 6H (90.4% vs 50.5%, respectively; risk ratio: 1.79; 95% CI: 1.62-1.97).[52] There were no significant differences for 3HP vs 6H in TB incidence (P = .32) and mortality (P = .43).

These data support use of 3HP as TB prophylaxis. It is not surprising that a much higher proportion of the 6H arm did not complete prophylaxis, because by 6 months, some people are simply tired of taking pills and stop.

WHIP3TB: Outcomes With 1 vs 2 Annual Rounds of Weekly Rifapentine Plus Isoniazid for 3 Months

Josep M. Llibre, MD, PhD:
Regarding the second objective, the study found no benefit from the second round of 3HP prophylaxis in Year 2.

Over 24 months, there were no significant differences for 1 vs 2 rounds of 3HP in TB incidence (P = .85; P = .98 for incidence from 12-24 months) and mortality (P = .13).[52] There was also no difference in the incidence of rifampicin-resistant TB over 24 months (P = .99).

WHIP3TB: Clinical Implications

Josep M. Llibre, MD, PhD:
This report had 2 important conclusions regarding TB prophylaxis in PWH living in areas with high TB endemicity.[52] First, this study demonstrated that 3HP has comparable efficacy and higher rates of treatment completion vs 6H. Second, the efficacy of 1 round of 3HP is comparable to 2 annual rounds of 3HP.

Laura Waters, MD:
I consider these to be extremely important findings supporting use of the shorter course for TB prophylaxis. That being said, do you think that 24 months was long enough to compare efficacy between 1 vs 2 rounds of 3HP? Could we potentially see differences emerge after, for example, 5 years?

Josep M. Llibre, MD, PhD:
That is a very important question, and the trial cannot answer it with a follow-up of only 2 years. Given that these PWH live in areas with highly endemic TB, it is plausible that additional rounds of prophylaxis with 3HP might be worthwhile over the longer term. We must await further data.

Regarding the implication of these results in Europe, we should first note that the prevalence of latent TB is estimated to be 13.7% in Europe overall.[54] In Spain, the prevalence of TB has declined markedly, with notification rates decreasing from more than 15.0 cases/100,000 individuals in 2009 to 9.8 cases/100,000 individuals in 2017.[56] Of the cases in 2017, 8.1% are in PWH. We are very happy with these trends because at the beginning of the HIV epidemic, TB was a very common opportunistic infection in PWH.

Laura Waters, MD:
There are similar trends in the United Kingdom. Our notification rates have decreased from more than 12.0 cases/100,000 individuals in 2009 to 8.5 cases/100,000 individuals in 2017, with only 3.0% of those recent cases being in PWH.[56]

REACT: Short vs Standard Duration of Sofosbuvir/Velpatasvir for Recent HCV Infection in PWID and PWH

Josep M. Llibre, MD, PhD:
Our final report covers an analysis by Matthews and colleagues[57] on the efficacy of short vs standard duration of HCV therapy for recently acquired HCV infection in persons who inject drugs (PWID) and PWH. The efficacy of shortened HCV therapy in this setting has been assessed before in nonrandomized studies. For example, the single-arm phase IIIb DAHHS2 trial reported a sustained virologic response rate at 12 weeks post treatment (SVR12) of 99% in patients with recently acquired HCV infection who were treated with grazoprevir/elbasvir for 8 weeks; this combination is currently approved by the European Medicines Agency (EMA) for a treatment duration of at least 12 weeks.[58,59]

The current analysis presented findings from the international phase III REACT noninferiority trial, which recruited PWID and PWH with recent primary HCV infection or reinfection, where the estimated duration of infection was 12 months or less.[57] After 6 weeks of treatment with sofosbuvir (SOF)/velpatasvir (VEL), the patients were randomized to stop treatment at Week 6 or continue treatment to Week 12. The 6-week duration of treatment is shorter than the EMA-approved regimen for SOF/VEL, which is a 12-week duration of treatment for all genotypes of HCV.[60]

Most unusually in this modern era of HCV treatment, the Data and Safety Monitoring Board stopped trial randomization because their second review in May 2019 found an unacceptably high rate of relapse in the investigational arm.[57] At that point, all enrolled, nonrandomized participants were immediately switched to the 12-week duration of therapy.

REACT: Patient Characteristics

Josep M. Llibre, MD, PhD:
Of the 192 participants in this analysis, most (69%) were HIV positive and of white race (83%).[57] The most common mode of exposure was sexual transmission with a same-sex partner (72%), followed by injection drug use (21%). A notable minority (37%) of the acute HCV cases were reinfections. The most common HCV genotype was genotype 1 (65%), followed by genotype 3 (17%), genotype 4 (16%), and then genotype 2 (3%). At baseline, the median duration of HCV infection was 25 weeks and the median HCV RNA level was 5.6 log10 IU/mL.

REACT: Inferiority of Short Duration of Sofosbuvir/Velpatasvir

Josep M. Llibre, MD, PhD:
The intention-to-treat (ITT) analysis found that the rate of relapse was 9% in the 6-week arm vs 2% in the 12-week arm. With modern direct-acting antivirals, we are accustomed to seeing a much lower relapse rate; for example, in the trials leading to EMA approval of SOF/VEL for 12 weeks across all genotypes, the relapse rate ranged from < 1% to 2%.[60]

In the modified ITT analysis, which excludes those lost to follow-up, death, and confirmed reinfections, the SVR12 rate was significantly lower in the 6-week vs 12-week arm (89% vs 98%, respectively; P = .021), translating to a difference of -8.8% (95% CI: -15.6% to -1.2%); the study's noninferiority margin was -12%.[57] These results show that the 6-week treatment duration was inferior to the 12-week duration.

When the investigators analyzed the characteristics of those who experienced viral relapse, they observed that these patients overall had a very high baseline level of HCV RNA, with a median of 6.7 vs 5.6 log10 IU/mL in the overall population.

REACT: Clinical Implications

Josep M. Llibre, MD, PhD:
My critique of this study is that there was no strong reason to expect that a shorter duration of treatment for recent HCV infection would be noninferior or even better than a longer duration of treatment. HCV has no reservoir and does not integrate into the genome.[61] Thus, the key variable for cure is the time needed for the host to achieve and maintain undetectable viremia. Once the virus is undetectable for a certain period of time on treatment, the infection is usually eradicated, and if it remains undetectable for 12 weeks after discontinuation of therapy, the host is cured. Clearly, 6 weeks is too short of a treatment duration to achieve eradication, and we should continue to administer HCV therapy for the standard duration of 8-12 weeks.

Laura Waters, MD:
It does seem clear that 6 weeks is too short for this regimen. An important rationale for early treatment of HCV, similar to HIV, is the anticipated public health benefit—effectively treatment as prevention to reduce the risk of onward transmission. However, it does not appear in this case that early treatment permits shorter duration of therapy.

Josep M. Llibre, MD, PhD:
I agree.

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