ViralEd - IAS 2021 eNewsletter

Unsuppressed plasma HIV-RNA viral load is associated with worse COVID-19 outcomes among people living with HIV (Nomah DK, et al; Abstract OALB0301)
Nomah and colleagues presented the results of COVID-19 outcomes in 13,142 PWHIV in the PISCIS cohort in 16 hospitals in Spain with a median age of 43.5 years, of whom 749 (5.7%) had SARS-CoV-2 infection. Of these, 103 (13.8%) were hospitalized, 7 (0.9%) went to ICU, and 13 (1.7%) died. Predictors of infection included migrant status, MSM, and multiple comorbidities. Severe illness and death were predicted by age >75 years and chronic co-morbidities. In patients with controlled viremia, CD4 cell counts did not predict severe illness, but low CD4 cell counts were associated with a significantly higher risk of severe illness in the presence of HIV viremia. These data add to the growing literature that shows a greater risk of severe COVID-19 illness among patients with low CD4 cell counts and/or uncontrolled viremia.

Long-acting subcutaneous lenacapavir dosed every 6 months as part of a combination regimen in treatment-naïve people with HIV: interim 16-week results of a randomized,
open-label, phase 2 induction-maintenance study (CALIBRATE)
(Gupta SK, et al; Abstract OALB0302)
Gupta and colleagues presented the planned 16-week interim analysis of the CALIBRATE Study of lenacapavir (LEN), the first capsid inhibitor, administered subcutaneously every 6 months following a 2-week lead-in in 182 treatment-naïve patients. This four-arm phase II study was randomized 2:2:2:1 and included a control group of BIC/TAF/FTC (group D) and three LEN groups: one receiving TAF/FTC for all 54 weeks (Group C), and two additional groups on LEN + TAF/FTC for 28 weeks that then will simplify to LEN + BIC (group B) or LEN + TAF (group A) in patients with virologic suppression. At entry, 15% had VL > 100,000, 93% were men, and 54% were black. After 16 weeks, VL <50 was achieved as follows: A 92%, B 94%, C 94%, and D 100%. Of 4 subjects with viremia, three patients (one in A and two in C) had <100 copies/mL and one in group B was >5,000 copies/mL. There were no grade 3-4 adverse events and no discontinuations due to adverse events, and grade 1-2 skin site reactions with pain and swelling occurred in 11-12% of patients. The study is on-going, and the achievement of early virologic suppression in over 90% in all arms is a promising outcome.

Switching to the 2-drug regimen of dolutegravir/lamivudine (DTG/3TC) fixed-dose combination (FDC) is non-inferior to continuing a 3-drug regimen through 24 weeks in a randomized clinical trial (SALSA) (Llibre JM, et al; Abstract OALB0303)
Llibre and colleagues presented the 24-week results of the SALSA study of a switch to DTG/3TC from a 3-drug regimen in 493 PWHIV, of whom 41% were non-white, 39% were women, and 39% were over age 50 years. The previous regimens included INSTIs (40%), NNRTIs (50%), and PIs (10%), and patients with previous virological failure or known NRTI or DTG resistance were excluded. DTG/3TC was non-inferior to the 3-drug regimen, and VL <50 copies/mL was achieved in 95% and 96% in the intervention and control arms, respectively. Discontinuations due to adverse events were uncommon (2% vs. 1%), and no unexpected AERs were observed. Weight gain of 2.1 kg was observed in the DTG/3TC arm and 0.6 kg in the control arm, and the investigators noted that 44% of patients were previously switched from TDF, and 32% from EFV, which may account for some of the observed weight gain. These data further support the efficacy of the two-drug regimen DTG/3TC in selected patients without past treatment failure or resistance to NRTIs or DTG.

More frequent viral load testing, with point-of-care tests has no impact on viral suppression in postpartum HIV-positive women in a randomized controlled trial in 2 clinics in Johannesburg, South Africa (Fairlie L, et al; Abstract OALB0402)
Fairlie and colleagues compared more frequent viral load testing (q 3 month) to q 6-month testing, the current standard of care, to prevent infant transmissions via breastfeeding in 405 post-partum women with HIV infection in South Africa. High rates of VL suppression of 89%-96% were achieved in both groups, with no significant difference overall or at any time point during the 18-month study period. This important finding in Johannesburg suggests that this prevention of mother-to-child transmission (PMTCT) program was successful at motivating post-partum women to maintain high adherence to achieve virologic suppression, although no additional benefit of more frequent viral load testing was observed.

Adherence to the dapivirine vaginal ring and oral PrEP among adolescent girls and young women in Africa: interim results from the REACH study (Nair G, et al; Abstract OALC01LB01)
Nair and colleagues presented interim analysis of adherence to the dapivirine ring and oral PrEP among 247 adolescent girls and young women in Africa from the REACH MTN-034 study. Adherence was assessed by remaining drug in the DPV rings and by dried blood spot for TDF. The average age was 18 years, and 35% of participants had one or more STIs. Study retention was 94% at 26 months. Moderate and high adherence to the ring was seen in 77.8% and 50.2% of ring users and 58.6% and 22.4% of oral PrEP users. More participants preferred the ring (88.5%) than oral PrEP (63.9%). To date there has been one HIV infection and four pregnancies. This study is unique for the higher level of adherence to oral PrEP in a cohort of young women in SSA, and both treatments were effective and well-tolerated.

High rates of drug resistance in individuals diagnosed with HIV in tenofovir disoproxil fumarate (TDF)-based pre-exposure prophylaxis rollout programs in Kenya, Zimbabwe,
Eswatini and South Africa (Parikh UM, et al; Abstract OALC01LB02)
Parikh and colleagues reported on the incidence of drug resistance in people with breakthrough infections in PrEP programs as part of the GEMS (Global Evaluation of Microbicide Sensitivity) project for drug resistance in PrEP in Africa. Of 175 patients, median age was 24 years, 74% were female, 21% were in serodiscordant couples, 10% were sex workers, 9% were MSM, and 6% were transgender. Detectable TFV-DP pK levels were present in 73% of samples, and 78% reported good or fair medication adherence. Of 104 evaluable patients, 45% had one or more resistance mutation, most commonly M184V (21%), K65R (3%), and K70EN (3%). These high frequencies of resistance mutations are reminders of the need for optimal adherence to oral PrEP to prevent both HIV infections and ART resistance. They are comparable to other recent reports of PrEP breakthroughs in other regions, and higher than the background prevalence of NRTI mutations in Africa. It will be critical to monitor trends in resistance following PrEP use in Africa and elsewhere to ensure that current ART practice patterns account for the growing use of PrEP.

Safety and pharmacokinetics of oral islatravir once monthly for HIV pre-exposure prophylaxis (PrEP): week 24 analysis of a phase 2a trial (Hillier S, et al; Abstract OALC01LB03)
Hillier and colleagues presented the 24-week safety and pK findings of a phase 2a study monthly oral islatravir at a 60 mg or 120 mg dose for the prevention of HIV infection in 242 individuals at low risk of HIV infection in a 2:2:1 randomization with a placebo arm. Study participants were 42% black, 53% white, with a median age of 31 years, and 67% female. The most common adverse events were headache (9%), nausea (5%), and diarrhea (5%), and were considered to be drug-related in 15% of patients. Two patients discontinued due to adverse effects, including rash and a foreign-body sensation. The most common lab abnormality was a grade 3 creatinine change in 4% of people. ISL triphosphate trough levels were above the threshold for PrEP activity for both doses. These findings suggest that once monthly dosing with islatravir achieves effective drug levels with a well-tolerated safety profile.

No impact of tenofovir/emtricitabine in estradiol exposure among transwomen on oral PrEP: results from the 12-week drug-drug interaction PrEParadas substudy
(Cattani V, et al; Abstract OALC0601)
Cattani and colleagues studied drug interactions between estradiol and PrEP in 24 transgender women in the PrEParadas study. Hormonal therapy was first initiated with drug levels, and then at day 15 PrEP was started followed by intensive pK sampling for 24 hours and a second pK evaluation at 12 weeks. The median age was 26, and the median BMI was 22.7%. 92% of subjects reported condomless anal sex within the past 6 months. No differences were seen in estradiol levels at baseline and at week 12. These data reinforce previous evidence that PrEP does not interfere with estradiol levels and may safely be used without significant drug interactions in transgender women.

Combination therapy with the broadly neutralizing antibody VRC07-523LS and the latency reversal agent Vorinostat fails to substantially reduce latent, resting CD4+ T cell infection
or reduce low-level viremia (Margolis DM, et al; Abstract OALA01LB03)
Margolis and colleagues reported the outcome of a combination of vorinostat, an oral agent that can reverse latency, and the broadly neutralizing antibody intravenous VRC07-523LS on the HIV reservoir in stable HIV patients on ART. The drugs were administered to eight patients in two cycles separated by at least 30 days. The drugs were well tolerated with no serious SAEs. No significant impact on the reservoir, as measured by Intact Proviral DNA assay (IPDA), and the frequency of resting CD4+ T-cell infection (QVOA), was observed, and low-level viremia persisted in one patient. Our search for effective drugs and strategies to reduce viral latency and clear viral reservoirs must continue.

Efficacy and safety of long-acting subcutaneous lenacapavir in phase 2/3 in heavily
treatment-experienced people with HIV: week 26 results (Capella study)
(Molina J-M, et al; Abstract OALX01LB02)
Molina and colleagues reported the 26-week results of the Capella study of lenacapavir when added to an optimized background in 72 heavily treatment-experienced patients with a median age of 52, median CD4 cell count of 150, mean VL of 4.17 log10 c/mL, and with proven drug resistance in 69%-99% of patients. The drug was administered by study staff initially in two 1.5 cc SQ injections, and some patients self-administered over time. Overall, 81% of patients achieved a viral load < 50 copies/mL, and 89% < 200 copies/mL. Outcomes by the number of active drugs in the background regimen were >2 - 81%, 1 - 86%, and 0 -67%. Resistance analysis could be performed on 31% of subjects, and resistance mutations were found in 4/11, including 4 pts with the M66I mutation, and single mutations with Q67H, K70N/R/S, and N75D. Median CD4 cells increased by 81 cells. There were no discontinuations due to AERs, and no serious AERS, and the most common side effects were diarrhea and nausea (8%) and headache (7%). Injection site reactions occurred in >20%, including swelling (26%) and erythema (24%), most were grade one and resolved within days, with a lower frequency of nodules lasting 1-2 weeks. These data clearly support the efficacy of LEN as a novel new class of drugs in ART experienced patients, and the occurrence of resistance underscores the importance of the identification of potent partners for combination therapy. The results of trials in naïve patients that are in process will be interesting.

Impact of COVID-19 on HIV treatment interruption in seven PEPFAR countries,
April - June 2020 (Mehta N, et al; Abstract OALX01LB04)
Mehta and colleagues captured the extraordinary and inspiring resilience of the global HIV care community in a study of the impact of COVID-19 on HIV treatment in seven PEPFAR countries in SSA - Zambia, Rwanda, Uganda, Botswana, Eswatini, Namibia, and Zimbabwe - by comparing pre-lockdown, lockdown, and post-lockdown treatment interruptions using program report data. Remarkably, while considerable variability across multiple countries was observed, treatment interruptions did not increase across these PEPFAR-supported countries with high ART coverage. The investigators attributed the maintenance of ART to flexibility and the adoption of innovative strategies to circumvent the barriers imposed by COVID-19, and these included ART dispensing for more than one month and community-based ART distribution. Other studies at this meeting showed a greater impact on new HIV testing, STI testing and treatment, and the earlier phases of the HIV care continuum, but one can only admire the exceptional response in the global HIV care community in finding creative ways to maintain ART during the COVID-19 pandemic.

SARS-CoV-2 immunity in COVID-19 convalescent individuals living with HIV: bulk immune profiling and SARS-CoV-2 specific humoral and cellular immune responses
(Polo ML, et al; Abstract OALA0101)
Polo and colleagues studied the immunological responses in 42 patients with known mild-moderate SARS-CoV-2 infection and compared 21 PWHIV to 21 HIV-negative controls. The median age was 47 and 41 years, respectively, and the median CD4 cell count in PWHIV was 513. All PWHIV were on ART. SARS-CoV-2 antibodies were detected in 75% of PWHIV and 85% of HIV negative controls. All patients had cellular responses to SARS-CoV-2, including individuals with no detectable antibody. PWHIV had signs of chronic immune activation and exhaustion, and higher CD4 cell counts were associated with higher SARS-CoV-2 antibodies and stronger cellular responses. These data offer a possible explanation for the observation of little difference in the clinical presentation of SARS-CoV-2 in PWHIV who are on ART and suppressed with higher CD4 cell counts, and reinforce the need for effective ART and ART adherence in PWHIV to reduce the risk of severe COVID-19 outcomes.

Single high-dose liposomal amphotericin-based regimen for treatment of HIV-associated Cryptococcal Meningitis: results of the phase-3 Ambition-cm Randomised Trial
(Lawrence DS, et al; Abstract OALB01LB03)
Lawrence and colleagues compared single high-dose liposomal amphotericin B, with flucytosine and fluconazole for 14 days, to a standard dose of amphotericin B plus flucytosine for 7 days followed by 7 days of fluconazole, for the treatment of cryptococcal meningitis. Both groups received consolidation therapy with fluconazole for 8 weeks. The primary endpoint was all-cause mortality at 10 weeks, and high-dose liposomal amphotericin B was 10 mg/kg compared to 1 mg/kg amphotericin B in the 7-day standard dose arm. The study population was 844 PWHIV in SSA, with median age 37, 60% male, and median CD4 27 cells/mL. Of 814 evaluable subjects, 24.8% died in the intervention arm and 28.7% in the control arm died, establishing the non-inferiority of the single high-dose regimen. The high dosage was well tolerated, and significantly fewer adverse effects were observed in the intervention arm, including less renal injury and anemia. If corroborated by additional studies, this study is likely to lead to changes in the WHO guidelines for the standard of care for the treatment of cryptococcal meningitis.

Preferences for implementing long-acting injectable pre-exposure prophylaxis among cisgender men who have sex with men in the US (Beckham SW, et al; Abstract OALC0502)
Beckham and colleagues surveyed 2,241 cis-gender MSM in the US about their preferences for long-acting injectable PrEP. Two thirds of respondents were age <30 years, 63% were white, and 60% lived in urban or rural settings. 84% had two or more sexual partners, 73% engaged in unprotected anal intercourse, and 14% had an STI history. 28% were on oral PrEP, and 76% were willing to try PrEP. The overall interest in long-acting injectable PrEP was high in 44% and moderate in 28%, and the most frequently reported potential barriers to use were side effects (52%) and cost (30%). Surprisingly, the site of injection, stigma, and the frequency of injections were of less importance (2%, 5%, and 11%, respectively). The cost threshold that was considered in the study was $100/month. These data offer important insights into the popularity and potential obstacles of long-acting PrEP in the United States.

Effectiveness and medication adherence of daily and event-driven pre-exposure prophylaxis regimens among Chinese men who have sex with men: a real-world CROPrEP study
(Xu J, et al; PECLB23)
Xu and colleagues presented the results of a comparison between daily (D) and event-driven (ED) PrEP in MSM in 4 cities in China. Of 1,222 screened MSM, 199 were excluded due to abnormal labs (84), HIV (5), HBV (13), and other reasons (97), leaving 1023 subjects who elected either daily and D or ED PrEP, and another 507 eligible non-users (NU) were also followed as part of the study. The median age of PrEP users was 29 years vs. 33 years for PrEP non-users, and PrEP users had higher risk behavior. PrEP reduced HIV incidence by 87% overall, and among adherent patients by 100%. HIV incident cases were 28 in non-users, compared to 7 in PrEP users (5 D and 2 ED), which were associated with incidence rates of 5.1/100 pt-yr (NU) and 0.6 (PrEP). Initial adherence was higher among daily PrEP users, 75% vs 57%, but the percentage of 'covered sex acts' improved over time with ED and fell over time with daily PrEP. These data support the efficacy of PrEP with both daily and event-driven PrEP among MSM in China, and demonstrate the utility of event-driven PrEP during times of lower sexual activity, as during the COVID-19 lockdowns during the study. Additional studies are needed on best practices to inform and engage at-risk MSM in PrEP use, as well as to retain MSM at risk on PrEP, in China where the stigma towards MSM remains high.


This activity is supported by an independent educational grant from Janssen Therapeutics, Division of Janssen Products LP.