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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children

Evidence Summary Table of Human Herpesvirus 8 Disease

Last Updated: December 15, 2016; Last Reviewed: December 15, 2016

Human Herpesvirus 8 Disease: PICO Question and Tabular Evidence Summary
Question I: Is there an indication for serologic testing for HHV-8 in asymptomatic HIV-infected children (compared with not testing) to guide clinical management?
Search terms: HIV, HHV-8, seroprevalence, HHV-8 diagnosis, pediatrics, KS
Reference Study Design (N)
Patient Characteristics Intervention Comparison Outcome Measures Main Findings Evidence Quality: 
  • Begin with basic study design.
  • Downgrade for risk of bias, imprecise estimates, inconsistency, and indirectness. 
  • Upgrade for large effect size and dose-response gradient, or if likely biases would reduce apparent effect.
 
Lennette et al 19961 Cross-sectional study

(N = 577)
U.S. 

HIV-positive adults

HIV-negative adults

HIV-negative children
None Risk groups HHV-8 Ab positivity to lytic and latent antigens 
Positive in <4% of those aged <15 years, and 18% to 28% of HIV-negative adults, 93% of HIV-positive MSM.
Observational. Downgraded for cross-sectional study design.
Albrecht et al 20042 Observational study

(N = 483)
German, HIV-positive adults
None KS-positive and KS-negative
HHV-8 Ab and HHV-8 DNA in PBMC
Abpositive in 91% with KS and 52% of those without. 12.3% adults were HHV-8 DNA-positive (45.5% in patients with KS and 7.8% in patients without KS). HHV-8 DNA positivity varied over time, in KS-positive and KS-negative adults.
Observational. Downgraded for indirectness (adults).
Laney et al 20043
Longitudinal observational study

(N = 87, including 42 with KS)
HHV-8/HIV coinfected adults
None KS-positive and KS-negative
HHV-8 DNA in oral fluid or PBMC
71% with KS, 56% without KS had at least 1 positive sample over 4 visits.
Observational. Downgraded for indirectness (adult study).
Question II: Among HIV-infected children, does initiation of ART (as compared with non-initiation) reduce the risk of KS?
Search terms: HIV, KS, antiretroviral therapy, pediatric, adult, treatment 
Kowalkowski et al 20154
Retrospective

(N = 25,529)


HIV-infected, male veterans on ART for at least 90 days
None Boosted PI- vs. NNRTI-based regimens
KS diagnosis >90 days after initiation of ART
Overall incidence rate of new KS while on ART low (2.02/1,000 py).

Longer duration of boosted PI reduced KS incidence after 1 year compared with NNRTI regimen. Increasing months on boosted PI was associated with lower KS. incidence (IRR = 0.79, CI 0.69–0.90).

Observational. Upgraded for large cohort size; downgraded for retrospective study and indirectness (adult study).
Vaz et al 20115
Retrospective 

(N = 32 with KS and 1,000 without)
HIV-infected children in Mozambique
None ART vs. no ART
KS diagnosis
32 children (out of approximately 3,000) not on ART diagnosed with KS over 5-year period; none of 1,000 children on ART during that time developed KS.
Observational. Upgraded for large magnitude of effect. Downgraded for retrospective study, lack of data on ART regimens, immunologic status, and length of ART.
Franceschi et al 20086
Retrospective

(N = 12,959)
Swiss HIV-positive adult cohort, KS-free at enrollment
None ART vs. no ART KS diagnosis
Pre-ART era (1984–1986) incidence: 33.3/1,000 py 

Early ART era (1996-1998) incidence: 5.1/1,000 py 

After 1999 incidence: 
1.4/1,000 py 

Risk increased in those off ART >3 months (HR8.14, 95% CI 4.01–16.54).

Observational. Upgraded for large cohort size and large magnitude of effect and dose-response gradient. Downgraded for retrospective study and indirectness (adult study).
Portsmouth et al 20037
Retrospective

(N = 8,640)
U.K. cohort; HIV-positive adults
None PI vs. NNRTI and both vs. no ART
KS diagnosis
Pre-ART era incidence: 30/1,000 py 

Since 2001 incidence: 0.03/1,000 py

Any ARV was protective, with exposure to PI or NNRTI equally so (adjusted RR 0.42 and 0.47 respectively).
Observational. Upgraded for large cohort size and large magnitude of effect and dose-response gradient. Downgraded for retrospective study and indirectness (adult study).
Question III: For HIV-infected patients initiating ART, are any specific ART regimens associated with lower rates of KS? 
Search terms: HIV, adult, KS, HHV-8, therapy, antiretroviral therapy, pediatric
Portsmouth et al 20037 Retrospective

(N = 8,640)
U.K. cohort; HIV-positive adults None PI vs. NNRTI and both vs. no ART
KS diagnosis
Pre-ART era incidence: 30/1,000 py 

Since 2001 incidence: 0.03/1,000 py

Any ARV was protective, with exposure to PI or NNRTI equally so (adjusted RR 0.42 and 0.47 respectively).
Observational. Upgraded for large cohort size and large magnitude of effect and dose-response gradient. Downgraded for retrospective study and indirectness (adult study).
Gantt et al 20148
Prospective, observational study

(N = 142)

HIV and HHV-8 coinfected men. Included some patients with already diagnosed KS (number not specified)
None PI vs. NNRTI ART
HHV-8 oropharyngeal shedding
26% of oral specimens positive. PI-based ART, but not NNRTI-based therapy, associated with lower frequency of DNA detection compared with no therapy (for PI: RR 0.2, 95% CI 0.1–0.5).
Observational. Upgraded for prospective design. Downgraded for indirectness (adult study).
Kowalkowski et al 20154 Retrospective

(N = 25,529)
HIV-infected male veterans, on ART for at least 90 days
None Boosted PI vs. NNRTI-based regimens
KS diagnosis >90 days after initiation of ART Overall incidence rate of new KS while on ART low (2.02/1,000 py).

Longer duration of boosted PI reduced KS incidence after 1 year compared with NNRTI regimen. Increasing months on boosted PI was associated with lower KS incidence (IRR = 0.79, CI 0.69–0.90).
Observational. Upgraded for large cohort size. Downgraded for retrospective study and indirectness (adult study).
Question IV: Among HIV-infected children with active KS, is treatment with ART (as compared with no ART) associated with higher rates of remission and/or decreased mortality?
Search terms: chemotherapy, Kaposi, children
Stefan et al 20119 Retrospective cohort 

(N = 70)
HIV-infected infants and children aged <14 years diagnosed with KS (South Africa)
ART and/or chemotherapy (vincristine, +/- bleomycin, +/- adriamycin)
Chemotherapy alone or none
Survival Treatment with ART was significantly associated with survival when compared with no ART (28/45 vs. 0/15), P<0.0001. 

Treatment with chemotherapy and ART was associated with a lower risk of death compared with chemotherapy alone, RR = 0.49; 95% CI 0.26–0.93.
Observational. Downgraded for retrospective design, variation in ART and chemotherapy regimens, and limited follow-up.
Gantt et al 201010
Retrospective cohort

(N = 73, only 32 with documented outcome)
HIV-infected children aged ≤18 years diagnosed with KS (Uganda)
ART and/or chemotherapy (vincristine +/- bleomycin)  ART or no ART
Complete or partial resolution of KS
Of the 32 patients with known outcome, higher proportion of those who received any ART regimen had complete resolution (19/26), compared with those who did not receive any ART ([1/6], P = 0.02).
Observational. Downgraded for retrospective design and majority of patients without documented outcomes.
Cox et al 201311
Retrospective cohort
(N = 81) 
HIV-infected children with KS (Botswana and Malawi)
ART and/or chemotherapy. 

Chemotherapy regimens:
doxorubicin, bleomycin, and vincristine (Botswana); Vincristine +/- bleomycin (Malawi).
ART alone, chemotherapy only, or none
Mortality at 12 months after KS diagnosis
Children who received chemotherapy and ART were less likely to die than children who received chemotherapy alone (RR = 0.44, 95% CI 0.23–0.85, per analysis in Anglemyer 2013). Severe immunosuppression independently associated with mortality. TIS staging did not correlate well with outcomes. 

ART and combination chemotherapy: 23 survived, 13 died (7 of 8 on the Botswana regimen achieved remission). 

ART only: 7 survived, 7 died. All children treated with ART with single-agent chemotherapy (14), chemotherapy only (2), and no treatment (3) died.
Observational. Downgraded for retrospective design, small sample size, and not designed to evaluate effect of choice of therapy or impact of severity of illness on choice of therapy.
Anglemyer 201412
Cochrane Review 

(4 retrospective cohort studies)
HIV-infected infants and children diagnosed with KS
Chemotherapy and ART
Chemotherapy alone
KS remission, death
Decreased risk of death among patients treated with chemotherapy and ART compared with chemotherapy alone, based on 2 retrospective cohort studies (RR = 0.46, 95% CI 0.29–0.73).
Meta-analysis of observational studies. Downgraded for paucity of and retrospective design of pediatric studies and inconsistent staging of KS. 
Question V: Among HIV-infected children with active KS, is treatment with chemotherapy in addition to ART (as compared with ART alone) associated with higher rates of remission and/or decreased mortality? 
Search terms: chemotherapy, Kaposi, children
Bower et al (2009)13
Prospective cohort 

(N = 254 overall), 163 stage T0 patients treated initially with ART alone
U.S. adults, 96% men,  with KS
ART alone as initial treatment Chemotherapy in addition to ART for those who failed on ART alone
Treatment-free survival, overall survival
High success of ART alone for stage T0: 1 patient died of KS; 37 (22%) required chemotherapy.
Observational. Upgraded for prospective design, large cohort size, demonstrates effect of tumor stage. Downgraded for indirectness (adult men).
Gantt et al 201010
Retrospective cohort

(N = 73, only 32 with documented outcome) 
HIV-infected children aged ≤18 years diagnosed with KS (Uganda)
ART and/or chemotherapy (vincristine +/- bleomycin)


ART or none
Complete or partial resolution of KS
Children with known outcomes were significantly more likely to have received chemotherapy or ART. Thirty of 32 patients with outcome data (93.8%) received chemotherapy. No differences in outcome were observed among those who received chemotherapy.
Observational. Downgraded for retrospective design, majority of patients without documented outcomes, no staging of disease, or insufficient data to detect effect of chemotherapy.
Vaz et al 20115
Retrospective cohort

(N = 28)
HIV-infected children diagnosed with KS (Mozambique)
ART and monthly paclitaxel
ART alone (1–3 months before initiating paclitaxel)
KS remission
19 children treated with ART and paclitaxel achieved complete and sustainable remission. None of the children improved while on ART alone, before starting paclitaxel.
Observational. Downgraded for retrospective design, limited sample size, and insufficient data to evaluate effect of chemotherapy.
Cox et al 201311
Retrospective cohort

(N = 81) 
HIV-infected children with KS (Botswana and Malawi)
ART and chemotherapy. 

Chemotherapy regimens:
doxorubicin, bleomycin, and vincristine (Botswana); vincristine +/- bleomycin (Malawi).
ART only, chemotherapy only, none
Mortality at 12 months after KS diagnosis
No difference in mortality for children who received chemotherapy and ART compared with children who received ART alone (RR = 0.72; 95% CI 0.37–1.43 per analysis in Anglemyer 2013).

Severe immunosuppression independently associated with mortality. TIS staging did not correlate well with outcomes. 

ART and combination chemotherapy: 23 survived, 13 died (7 of 8 on the regimen used in Botswana achieved remission). 
Observational. Downgraded for retrospective design and small sample; not designed to evaluate effect of choice of therapy.
Anglemyer 201412
Cochrane Review 

(4 retrospective cohort studies)
HIV-infected infants and children diagnosed with KS
Chemotherapy plus ART
ART alone
Response to treatment, mortality
Chemotherapy plus ART associated with complete or partial response to treatment based on 2 studies (RR 5.75, 95% CI 1.59-20.73). No significant difference in mortality risk based on 1 study (RR 0.72, 95% CI 0.37-1.43).
Meta-analysis of observational studies. Downgraded for paucity of and retrospective design of pediatric studies and inconsistent staging of KS. Unclear if early, localized KS can be adequately treated with ART alone.
Letang et al 201314
Pooled analysis of 3 prospective cohorts 

(N = 417)
ART-naive, HIV-infected adults with KS, including 58 with KS-IRIS (South Africa, Zimbabwe, Mozambique, U.K.)
ART and chemotherapy
ART alone
Mortality
Lack of chemotherapy during pre-ART or follow-up period associated with higher mortality (HR 2.35, 95% CI 1.09–5.05). Greater risk of KS-IRIS among those who received ART alone (HR 2.97, 95% CI 1.02–8.69).

Overall KS mortality rate 3.3-fold higher in African cohorts than in U.K.; all KS-IRIS mortality occurred in African cohorts. African KS-IRIS patients had 6.4-fold higher mortality than other African KS patients. 
Observational. Upgraded for relatively large sample size and prospective design including African and U.K. cohorts. Downgraded for indirectness (adults).
Mosam et al 201215
Randomized controlled trial 

(N = 112)
ART-naive HIV-infected adults with KS (South Africa)
ART and chemotherapy
ART alone
Overall KS response (using AIDS Clinical Trial Group criteria) 12 months after ART initiation. Secondary outcomes included time to response, progression-free survival, overall survival.  ART and chemotherapy produced higher overall KS response over 12 months (66% vs 39%, difference 27% [95% CI 9%–43%]). At 12 months, no difference in survival, viral load, CD4 cell counts between the treatment groups. Quality of life measures improved in all patients.
Strong RCT design and relatively large sample size. Downgraded for indirectness (adults). 
Question VI: Among HIV-infected children treated with ART who develop IRIS, is chemotherapy in addition to continuation of ART (compared with no chemotherapy) associated with higher rates of remission and/or decreased mortality?
Search terms: Kaposi, IRIS
 
Cox et al 201311
Retrospective cohort

(N = 81)
HIV-infected children with KS (Botswana and Malawi)
ART and chemotherapy. 

Chemotherapy regimens: doxorubicin, bleomycin, and vincristine (Botswana); vincristine +/- bleomycin (Malawi).
ART only, chemotherapy only, none
Mortality at 12 months after KS diagnosis
KS-IRIS was diagnosed in 18 (22%) of KS patients. Did not describe treatment regimens or outcomes of KS-IRIS patients.
Observational. Downgraded for retrospective design and small sample. Not designed to evaluate effect of choice of therapy.
Letang et al 201314
Pooled analysis of three prospective cohorts

(N = 417)
ART-naive HIV-infected adults with KS, including 58 with KS-IRIS (South Africa, Zimbabwe, Mozambique, U.K.)
ART and chemotherapy
ART alone
Mortality
Lack of chemotherapy during pre-ART or follow-up period associated with higher mortality (HR 2.35, 95% CI 1.09–5.05). Greater risk of KS-IRIS among those who received ART alone (HR 2.97, 95% CI 1.02–8.69).

Overall KS mortality rate 3.3-fold higher in African cohorts than in U.K.; all KS-IRIS mortality occurred in African cohorts. African KS-IRIS patients had 6.4-fold higher mortality than other African KS patients. 
Observational. Upgraded for relatively large sample size and prospective design including African and U.K. cohorts. Downgraded for indirectness (adults).
Letang et al 201016
Prospective observational study

(N = 69, including 8 with KS-IRIS)
Adults with HIV and HHV-8 (seropositive or with clinical KS), initiation of ART (Mozambique)
ART plus systemic chemotherapy or ART alone
None Partial or complete clinical response
8 cases of KS-IRIS were observed, treated with either ART alone (1) or ART plus chemotherapy (6). Partial or complete clinical response in 5/8 patients overall (62.5%).
Observational. Upgraded for prospective design. Downgraded for small sample size and indirectness (adults). Not designed to evaluate effect of choice of therapy.
Question VII: Among HIV-infected children who achieve remission from KS, what therapies are recommended to lower the risk of recurrence?
Search terms: KS, treatment, recurrence, HIV
Martin-Carbonero et al 200817
Retrospective, adult study

(N = 61)
HIV-infected Spanish adults with diagnosed KS, treated with ART and pegylated doxorubicin and achieved remission
ART plus doxorubicin
None Survival and recurrence
13% had relapse (13.5%/year).
Observational. Downgraded for retrospective data, indirectness (adult study) and lack of comparison data for subjects not on ART.
Gotti et al 201418 Retrospective

(N = 184)
HIV-infected Italian adults with KS (part of a larger study on survival among HIV-positive adults with cancer)
None ART vs. no ART following KS diagnosis
Survival
Multivariate model: lower mortality after KS associated with ART (HR 0.3, 0.15–0.78, P = 0.011). Observational. Upgraded for large magnitude of effect. Downgraded for retrospective data, indirectness (adult study), and lack of data for specific chemotherapy or ART regimens.
Key to Acronyms: ART = antiretroviral therapy; ARV = antiretroviral; CD4 = CD4 T lymphocyte cell; CI = confidence interval; HHV-8 = human herpesvirus 8; HR = hazard ratio; KS = Kaposi sarcoma; IRIS = immune reconstitution inflammatory syndrome; MSM = men who have sex with men; NNRTI = non-nucleoside reverse transcriptase inhibitor; PBMC = peripheral blood mononuclear cells; PI = protease inhibitor; py = person years; RR = relative risk

References

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