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Literature Review HIV Homepage: Global Tuberculosis Control: WHO Report 2007 www.globalhealthreporting.org/tb.asp): This is the WHO Report for TB for 2007. Highlights are the following:
The Global TB Epidemic
- There were an estimated 8.8 million new cases of tuberculosis in 2005 including 7. million in Asia and sub-Saharan Africa.
- There were a total of 1.6 million deaths due to tuberculosis including 195,000 persons with HIV.
- The TB incidence rate for 2005 was stable or declining in all six WHO regions.
DOTS and “Stop TB Strategy”
- DOTS is the major component of the “Stop TB Strategy” and was applied in 187 of 212 countries in 2005; these represent 89% of the world population.
- The number of cases of HIV co-infection and multidrug-resistant TB (MDR-TB) diagnosed and treated in 2005 was increasing, but was substantially below the Global Plan for 2006. HIV testing in TB patients was increasing in the African Region, but little effort was made to screen HIV-infected persons for TB.
- Facilities to diagnose and treat MDR-TB are not widely available and the scale of XDR-TB is not well known.
- (^) Treatment of MDR-TB was reported as successful in about 60% by the Green Light Committee.
- The Stop TB Strategy emphasizes linkages between national TB programs with health care providers and communities, but no country succeeded in making all of the recommended activities operational on a national scale.
Financing Control
- Funds for TB control totaled $2 million in 2007, but the requirements for the Global Plan would require an additional $1.1 billion.
- Six countries accounted for three fourths of the total national TB control programs: Brazil, Russia, China, South Africa, India and Indonesia. The biggest increases in the past five years have been domestic funding from China, Russia and South Africa.
Targets and Goals
- It appears that the incidence rate of TB in the world is falling which suggests that the target for 2015 has already been achieved. Nevertheless, the decline is not sufficiently fast to meet the impact targets of the “Stop TB Partnership”.
- Targets for the DOTS programs were for 70% case detection and 85% for cure; case detection rates were 60% and treatment success was 84% for 2005 indicating both targets were close to the goal.
Results by Region: The following table indicates the incidence, prevalence and mortality for tuberculosis for six regions. The table also includes the totals for the globe and the prevalence of HIV in incident cases of TB.
Global Tuberculosis Control: WHO Report 2007 (www.globalhealthreporting.org/tb.asp)
Incidence Prevalence Mort.
Region
Population (x 1000)
No. x 1000
/100, /year
No. x 1000
/100, /year
/100, Year
HIV prevalence in incident cases
Africa Americas E. Med. Europe S.E. Asia W. Pacific
738, 890, 541, 882, 1,656, 1,752,
2, 352 565 445 2, 1,
343 39 104 50 181 110
3, 448 881 525 4, 3,
511 50 163 60 290 206
74
21
31 17
28
Globe 6,461,751 8,811 136 14,052 217 24 11
High Burden Countries: The report separates 22 countries which account for approximately 80% of the new and relapse cases data from these countries and for the world are summarized in the following table:
High burden Countries Globe
New & relapse cases (x 1000) Incidence /100,000/year Mortality /100,000/year HIV prevalence % population covered by DOTS 1995 2005 Case detection-smear positive Treatment success (2004)
Tuberculosis and HIV: The frequency of such co-infections is highly variable in different regions. The highest rates of HIV in incident TB cases are in Africa, including Zimbabwe-60%, South Africa-58%, Mozambique-50%, Uganda-30%, Tanzania-29% and Kenya-28%. The rate for all of Africa is 28% for the Americas is 7.9%, for Europe-4.6% and for Southeast Asia-3.9%. The following table summarizes some of the data in the WHO report relevant to this issue. To better understand the table, the columns indicate the number of TB cases that are tested for HIV, the percent of these tests that are positive, the percent of total known infections for the estimated total (for Africa this would mean that only 13% of those tested are thought to represent the total co-infected pool), the percent of persons with co-infections who are receiving antiretroviral therapy and the percent of the total (for example, Africa accounts for approximately 80% of all co-infected patients):
HIV and TB
No. tested HIV + TB/ % of total
suppression with HIV RNA counts of less than 400 c/ml with CD4 cell count monitoring for up to six years. The data were stratified based on the baseline CD4 cell count.
Results: The analysis was based on observations of 655 patients observed for a median of 46 months. The results showed that the median change from baseline CD4 cell count at six years was an increase of 274/mm^3 , and the final CD4 cell count correlated strongly with the baseline CD4 cell count as indicated in the following table:
No. Baseline
Median CD4 count at 6 Year Follow-up % > 500/mm^3 345 152 158
493/mm^3 508/mm^3 829/mm^3
Conclusion: The authors concluded that only patients with a baseline CD4 cell count exceeding 350/mm^3 were likely to achieve a nearly normal CD4 cell count with six years of HAART. They further suggest that these data support initiation of HAART at an earlier point in the CD4 cell count decline in order to achieve a more normal immunologic recovery.
Homepage: Male circumcision for HIV prevention in men in Rakai, Uganda: a randomized trial [Gray RH Lancet 2007;369:657]: The authors investigate the potential role of male circumcision to reduce HIV incidence in men.
Methods: The study included 4,996 uncircumcised, HIV-negative men age 15-49 years who agreed to HIV testing and surgery in the Rakai district of Uganda. The participants were randomly assigned to immediate circumcision or a delay for 24 months. The primary outcome was HIV incidence based on HIV serology at 6, 12 and 24 months.
Results: The 24 month results showed a relative risk of 0.51 (p = 0.006). The two fold reduction was significant for the entire group, and also significant for subsets based on sociodemographics, behavior and STDs. There were adverse events in 3.6% receiving circumcisions, but all resolved with treatment. The post-test analysis showed that behaviors were similar in all groups. Details are provided in the following table:
No.
Incidence HIV at 24 months (/100 person-years) Efficacy Circumcision 2474 2522
Conclusions: The authors that male circumcision reduces the incidence of HIV infection without behavior disinhibition.
Homepage: Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomized controlled trial [Bailey RC Lancet 2007;369:643]: This was another randomized controlled trial of circumcision, this with 2,784 participants from Kisumu, Kenya who were randomly assigned to immediate circumcision or delayed for 24 months. The study was prematurely stopped due to excessive rates of HIV infection in the control group: 4.2% vs. 2.1% (p = 0.007). This represents a risk reduction of 53% and the details are shown in the following table:
No.
No. with HIV
Two Year Incidence
Adverse Event
Circumcision Controls
The authors conclude that circumcision significantly reduces the risk of HIV transmission to young men in Africa.
Comment: There are now at least three trials demonstrating reductions in HIV transmission from female to male following male circumcision with protective effects at 50-76% (Auvert B PLoS Med 2005;2:1; Gray RH Lancet 2007;369:657 and Bailey RC Lancet 2007;369:643). These results are consistent with observational studies (Weiss HA AIDS 2000;14:2361; Siegfried N Lancet Infect Dis 2005;5:165) and is biologically plausible (Donoval BA Am J Clin Pathol 2006;125:386; McCoombe SG AIDS 2006;20:1491). It is noted in the discussion of the paper by R Bailey et al. that the assumption of a 60% protective effect could reduce the number of new HIV infections by two million and avert 300,000 deaths in sub-Saharan Africa over the next ten years (Williams BG PLoS Med 2006;3:e262). The cost analysis suggests a saving of about 2.4 million dollars over 20 years for each 1,000 circumcisions (Kahn JG PLoS Med 2006;3:e517). It is noted that the adverse event rate in these three studies varied from 1.5% to 3.6%, but the studies were done with highly trained practitioners so that generalization of these low rates with virtually no permanent sequelae may not be appropriate. It would appear that additional studies to demonstrate efficacy are unnecessary and that the major issues at present at the assurance of high surgical standards, low cost, and clear understanding that the procedure reduces risk of HIV transmission, but does not eliminate it so that other precautions including condoms are still necessary. A further issue concerns acceptability of circumcision which could show great variation across African communities and might be very different in other populations such as Southeast Asia (Newell M-L Lancet 2007;369:617). An additional issue concerns the value of this procedure in prevention of male-to-female HIV transmission which is still under study. Homepage: Scientists rethink approach to HIV gels [E Check Nature 2007;446:12]: The author reviews the status of microbicide gels as a method to prevent HIV transmission in women in the light of the announced failure of the clinical trial using cellulose sulphate vaginal gel in February, 2007. This is the third large clinical trial of a microcibide gel that failed: the savvy gel failed, the cellulose sulphate gel actually led to higher HIV infection rates and the spermicide nonoxynol-9 also led to higher HIV transmission rates. The concern in the review is the impression that these trials are expensive and complex, but represent a product selection that may be premature in the hast to get a product. In fact, there are “dozens of candidate microbicides” under development. The conclusion here is that the most
virologic failure decreased from 23% in 1996 to 8% in 2002 (Lampe FC Arch Intern Med 2006;166:521).
- The concern about drug resistance and loss of treatment options is now tempered by the observation that resistance is evolving slowly and new drugs are being developed.
Recommendations: The authors recommend that guidelines should advocate initiating antiretroviral treatment when the CD4 cell count is 350/mm 3 “so long as the patient is ready”.
Homepage: HIV Type 1 Chemokine Coreceptor Use among Antiretroviral-Experienced Patients Screened for a Clinical Trial of a CCR5 Inhibitor: AIDS Clinical Trial Group A5211 [Wilkin TJ Clin Infect Dis 2007;44:591]: The goal of the study was to screen patients for chemokine coreceptor for participation in a phase 2b study of the investigational CCR inhibitor vicriviroc.
Methods: ACTG protocol A5211 is a phase 2b study of CCR5 inhibitor vicriviroc with the following eligibility criteria: failure of at least one-three drug regimen, current HIV viral load exceeding 5000 c/ml and current treatment with a boosted PI. The coreceptor phenotype assay was done by Trofile (Monogram Biosciences).
Results: Results are summarized in the following table which shows that approximately 50% of the participants were CCR5 only and the rest were dual-tropic or mixed, or CXCR only.
Coreceptor phenotype
Coreceptor Number Median CD Total CCR5 only Dual-tropic or mixed (D/M) CXCR4 only No result
170/mm^3
103/mm^3
161/mm^3
*12 of 118 were retested at a median of 37 days later and found to have D/M virus **Baseline CD4 count was significantly lower (103/mm 3 ) compared to CCR5 only (170/
mm^3 ) (p < 0.001).
Of note is that 12 of 118 patients who were originally shown to be CCR5 only showed D/M virus on retesting at periods up to 42 days later. The most important correlate with coreceptor phenotype was the CD4 cell count as shown in the table.
Conclusions: The authors conclude that dual-tropic or mixed HIV-1 populations that use both CCR5 and CXCR4 is common in highly treatment-experienced patients and that the D/ M group showed significantly lower CD4 cell counts.
Comment: As noted by the author, the results in this trial were similar to those of TORO1&2 in showing high rates of D/M or X4 virus with increasing treatment experience. For treatment-naïve patients, prior reports using the Trofile assay indicated over 80% had R strains and less than one percent had X4 strains (Moyle GJ J Infect Dis 2005;191:866). The results of this trial are obviously highly relevant for patient selection with the anticipated introduction of maraviroc and vicriviroc into clinical practice.
Homepage: Timing of Antiretroviral Therapy Initiation in Tuberculosis Patients With AIDS: A Decision Analysis [Schiffer JT J Acquir Immune Defic Syndr 2007;44:229]: The authors address the issue of timing of antiretroviral therapy in patients with TB co-infection.
Methods: The authors conducted a decision analysis in a hypothetical cohort of 1, patients with a CD4 cell count less than 200/mm 3 with standard TB therapy (DOT for six months) with three variables in HAART: 1) HAART started in the first two months of TB therapy; 2) HAART delayed until month 3-6 and 3) no HAART. There were two outcomes: first was the all-cause mortality within 12 months of starting TB therapy and the second was “combined outcome” which included mortality, new AIDS-defining conditions, severe IRIS and grade 3/4 adverse drug reactions.
Results: The results favored early HAART on the basis of a reduction in mortality; the “combined outcome” was nearly the same for all three strategies. Early HAART was favored even with the highest rates of IRIS (70%) and the highest rates of severe drug toxicity (56%). The deferred HAART was favored only if the IRIS-related mortality in the early group exceeded 4.6%. Details of the analysis are in the following table:
Outcomes at 1 year for 1000 patients with TB/HIV co-infection and CD4 count < 200/mm 3
Early HAART (1 st^ 2 months)
Deferred HAART (2-6 months) No HAART
Mortality* 33 48 147
Mortality plus
AIDS event Severe IRIS
