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IAS 2011: Anti-Herpes Drugs Reduce HIV Viral Load, Slow Disease Progression

Several studies presented at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011) last month in Rome showed that treating herpes simplex virus type 2 (HSV-2) with acyclovir or valacyclovir (Valtrex) reduced HIV viral load and slowed disease progression.

Results were so consistent that Jeffrey Lennox, rapporteur for the clinical science track, quipped, "I am officially declaring 2011 the year of acyclovir."

Acyclovir and Disease Progression

Numerous studies have explored whether treating HSV-2 -- the usual cause of genital herpes -- could reduce the risk of HIV infection, with mixed results. But the effect of HSV treatment on progression of existing HIV disease appears more consistently promising.

Steve Reynolds from the U.S. National Institute of Allergy and Infectious Diseases (NIAID) and colleagues (abstract TUAB0104) conducted a randomized, placebo-controlled trial to test whether HSV-2 suppressive therapy would affect HIV disease progression in people who are not on antiretroviral therapy (ART).

Given that an estimated 20 million HIV positive people in sub-Saharan Africa are not yet receiving ART, either due to lack of access or because they do not yet have a CD4 count or symptoms that meet the threshold for treatment initiation, strategies to delay disease progression could be beneficial as ART provision is scaled up, the researchers suggested.

This analysis included 440 HIV-1 and HSV-2 coinfected adults in Rakai, Uganda, who had CD4 T-cell counts of 300-400 cells/mm³ and were not yet on ART. (The treatment threshold in Uganda was 250 cells/mm³ at when the study started, but now matches the World Health Organization [WHO] guidelines threshold of 350 cells/mm³.)

About 70% of study participants were women and the average age was about 35 years. At study entry the median viral load was about 4.44 log. Participants were randomized (1:1) to receive either 400 mg oral acyclovir or placebo twice-daily, and followed for a median of 24 months.

Results

• Overall, 95 participants in the acyclovir arm and 110 in the placebo arm reached the primary endpoint of CD4 count below 250 cells/mm³ or ART initiation due to WHO stage 4 disease.
• This represented a significant risk reduction of 27% (adjusted hazard ratio [aHR] 0.73).
• In a sub-analysis stratified by baseline HIV viral load, the 2 highest quintiles -- above 50,000 copies/mL -- showed the strongest protective effect (aHR 0.62, or a 38% reduction).
• The lowest 2 HIV viral load quintiles, in contrast, showed no efficacy for acyclovir in reducing HIV progression (HR 0.90, a non-significant reduction of 10%).
• Overall, HIV viral load rose by +0.4 log in the acyclovir group while falling by -0.06 log in the placebo group.
• No serious adverse events were observed.

"Suppressive acyclovir may be warranted among HSV-2/HIV-1 dually infected individuals not yet on antiretroviral treatment, particularly among those with high viral loads," the researchers concluded.

Acyclovir vs Valacyclovir

In a related poster presentation, Kenneth Mugwanya from Makerere University in Kampala and colleagues (abstract WEPDB0106) compared the efficacy of high-dose valacyclovir HSV-2 suppressive therapy vs standard-dose acyclovir.

This randomized, open-label trial enrolled 32 HIV-1/HSV-2 coinfected participants; about half were women and the median age was 37 years. They were ART-naive, had CD4 counts above 250 cells/mm³ (median 441 cells/mm³), and a mean HIV viral load of 4.10 log.

Participants were randomly assigned to take 400 mg twice-daily acyclovir or 1.5 g twice-daily valacyclovir for 12 weeks. They then underwent a 2-week wash-out period and switched to the alternative regimen for 12 more weeks.

Results

• After 12 weeks of treatment, mean HIV viral load was 2.94 log in the valacyclovir arm vs 3.56 log in the acyclovir arm, or 4-fold lower.
• HIV levels fell by -1.23 log -- or 17-fold -- in the valacyclovir arm compared with a drop of -0.56 log -- or 3.5-fold -- in the acyclovir arm.
• Participants had undetectable HIV (< 40 copies/mL) during 13.5% of weeks on valacyclovir compared with just 3.2% of weeks on acyclovir.
• Adherence was similar and excellent in both arms, with pill counts showing better than 99% adherence.

These findings led the investigators to conclude, "The potential for higher dose HSV-2 suppressive therapy to slow HIV-1 disease progression among HIV-1/HSV-2 coinfected persons not yet eligible for antiretroviral therapy warrants further evaluation."

Valacyclovir is about 10 times more expensive, however, which makes it less accessible than the older and cheaper generic acyclovir.

Valacyclovir during Pregnancy and Breastfeeding

Alison Drake from the University of Washington in Seattle and colleagues (abstract MOAC0201) looked at HIV levels in plasma and breast milk among HIV-1/HSV-2 coinfected women who had recently given birth.

This study enrolled 148 pregnant women (average age 25 years) in Nairobi, Kenya, who had CD4 counts above 250 cells/mm³, WHO Stage 1 or 2 (mild) disease, and were not yet on ART except for zidovudine (AZT; Retrovir), single-dose nevirapine (Viramune), and lamivudine to prevent mother-to-child HIV transmission. At baseline the mean plasma HIV viral load was 3.94 log.

Starting at 34 weeks gestation, participants were randomly assigned to take 500 mg twice-daily valacyclovir or placebo during late pregnancy and continuing through 12 months after delivery. HIV RNA was measured at 2, 6, and 14 weeks and 6 months postpartum.

Results

• Women who took valacyclovir were less likely to have HIV RNA detected in their breast milk at 6 and 14 weeks compared with those in the placebo group.
• The likelihood of detectable HIV in breast milk of valacyclovir recipients was 30% lower at week 6 and 46% lower at week 14.
• At 6 months postpartum, plasma HIV RNA levels were 0.41 log lower in the valacyclovir arm than in the placebo arm.
• However, the 12 month mother-to-child HIV transmission rate was 7% overall, and did not differ based on whether women took valacyclovir or placebo.

This research team concluded, "Valacyclovir significantly decreased breast milk and postpartum plasma HIV-1 RNA and could be a useful adjunct with short-course antiretrovirals in resource-limited settings."

Looking at the same cohort of women, Alison Roxby, also from the University of Washington and colleagues (abstract TUAB0202) presented findings on HIV disease progression.

The researchers measured CD4 cell counts and viral load at baseline (34 weeks gestation) and 12 months after giving birth. Median baseline CD4 counts were 452 cells/mm³ in the valacyclovir arm and 481 cells/mm³ in the placebo arm.

Results

• Over 12 months of follow-up, CD4 levels increased more in the valacyclovir arm, ending up 73 cells/mm³ higher.
• From a similar baseline, HIV viral load increased by +0.27 log in the valacyclovir arm and by +0.67 log in the placebo arm, ending up 0.40 log lower in the active treatment arm.
• Numbers of cases of tuberculosis (4 women in the valacyclovir arm, 2 in the placebo arm) and deaths (1 in the valacyclovir arm, 2 in the placebo arm) were not significantly different, however.

"Valacyclovir suppression during pregnancy and breastfeeding may improve long-term outcomes for HIV-1/HSV-2 coinfected women and their infants," the reseachers concluded.

Even at a higher price than acyclovir, valacyclovir can be a cost-effective option in resource-limited settings lacking full access to ART, Roxby said. A mathematical model suggested that HIV viral load reductions of the magnitude seen in this study could lengthen the time to development of AIDS by 1.9 years in asymptomatic patients.

Investigator affiliations:

Reynolds study: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Division of Intramural Research, Bethesda, MD; Johns Hopkins University School of Medicine, Division of Infectious Diseases, Baltimore, MD; Makerere University College of Health Sciences, Kampala, Uganda; SAIC-Frederick Inc., Clinical Monitoring Research Group, Frederick, MD; Rakai Health Sciences Program, Kalisizo, Uganda; Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Mugwanya study: Infectious Diseases Institute, Makerere University, Kampala, Uganda; University of Washington, Global Health, Seattle, WA; University of Washington, Medicine, Seattle, WA; University of Washington, Epidemiology, Seattle, WA; Kenyatta National Hospital, Nairobi, Kenya.

Drake study: University of Washington, Global Health, Seattle, WA; University of Washington, Medicine, Seattle, WA; University of Nairobi, Obstetrics and Gynecology, Nairobi, Kenya; University of Washington, Epidemiology, Seattle, WA; University of Washington, Biostatistics, Seattle, WA; Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA.

Roxby study: University of Washington, Department of Medicine, Seattle, WA; University of Washington, Department of Global Health, Seattle, WA; University of Nairobi, Department of Obstetrics and Gynecology, Nairobi, Kenya; University of Washington, Departments of Biostatistics and Global Health, Seattle, WA; University of Washington, Departments of Medicine, Epidemiology, and Global Health, Seattle, WA.

8/2/11

References

S Reynolds, F Makumbi, N Kiwanuka, et al. Impact of HSV-2 suppressive therapy with daily acyclovir on HIV-1 disease progression: a randomized placebo-controlled trial in Rakai, Uganda. 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011). Rome, July 17-20, 2011. Abstract. TUAB0104.

K Mugwanya, J Baeten, N Mugo, et al. High-dose valacyclovir suppressive therapy results in greater reduction in plasma HIV-1 levels compared to standard dose acyclovir suppression among HIV-1/HSV-2 co-infected persons: a randomized, open-label, crossover trial. 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011). Rome, July 17-20, 2011. Abstract WEPDB0106.

A Drake, A Roxby, F Ongecha-Owuor, et al. Valacyclovir suppression reduces breast milk and plasma HIV-1 RNA postpartum: results of a randomized clinical trial. 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011). Rome, July 17-20, 2011. Abstract MOAC0201.

A Roxby, A Drake, F Ongecha-Owuor, et al. Peripartum valacyclovir improves markers of HIV-1 disease progression in women co-infected with HSV-2: a randomized trial. 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011). Rome, July 17-20, 2011. Abstract TUAB0202.